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Classifications

Harrison's Part

Mechanistic Nosology

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Both families are biallelic. The 2015 sisters are homozygous for a single missense allele; the 2022 patient is compound heterozygous for a nonsense and a missense allele. MRPS7 is nuclear-encoded and autosomal, so despite the mitochondrial phenotype this is a nuclear recessive disease with a 25 percent sibling recurrence risk and no maternal transmission.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings."

Homozygosity for one allele in both affected siblings, which is the recessive segregation in the first family.

PMID:36421788 SUPPORT Human Clinical

"Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His)."

The second family's biallelic configuration, which is compound heterozygous rather than homozygous - so the recessive claim does not rest on consanguinity alone.

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Discussions and Knowledge Gaps

2

Is COXPD34 a separate entity from MRPS7-related Perrault syndrome, or are they one disease ascertained at two ages?

OPEN QUESTION OPEN coxpd34_two_entities_one_gene

Attached to

disease#Combined Oxidative Phosphorylation Deficiency 34 phenotypes#Premature Ovarian Insufficiency

The three published MRPS7 patients are all female, all have sensorineural hearing loss, and the two who reached reproductive age both have premature ovarian insufficiency. That is Perrault syndrome in two of three. What separates the OMIM 617872 phenotype is the hepatorenal failure of the severely affected sister - and she died before her reproductive phenotype could be known, so nobody can say whether she would also have had POI. Read one way, MRPS7 causes a single disease whose severe end kills in adolescence and whose mild end presents to a fertility clinic, and the two names are an artefact of which specialist saw the patient. Read the other way, the hepatorenal course is a genuinely distinct presentation deserving its own entity. dismech currently curates both readings - this entry and the MRPS7 gene record in `Perrault_Syndrome` - which is honest about the uncertainty but means the same three patients appear in two places. Three patients is not enough to settle it; a fourth family, particularly one with a male sibling or with a liver phenotype ascertained after puberty, would be.

Do the 2022 MRPS7 alleles cause a mitoribosomal defect, or are they only predicted to?

KNOWLEDGE GAP OPEN coxpd34_limited_gene_disease_validity

Attached to

pathophysiology#Biallelic MRPS7 Variants

ClinGen classifies MRPS7 against mitochondrial disease as Limited, and OMIM flags the gene-phenotype mapping as provisional. The reason is visible in the two reports: all of the functional evidence - impaired translation, reduced 12S rRNA, complementation rescue - comes from a single family homozygous for one missense allele. The second family's nonsense and missense alleles were called pathogenic on in-silico prediction alone, with no protein, transcript, assembly or respiratory-chain measurement. A single functional study of the p.(Lys125*) and p.(Arg179His) alleles would move this relationship materially, and is the cheapest available way to do so.

Proposed experiments

Functional characterisation of the 2022 MRPS7 alleles

exp_coxpd34_second_family_function

Measure MRPS7 protein and transcript abundance, mitoribosomal small-subunit assembly by sucrose-gradient or complexome profiling, mitochondrial translation by pulse labelling, and respiratory-chain enzyme activities in fibroblasts from the compound-heterozygous 2022 patient, with wild-type MRPS7 complementation as the control - reproducing in that family the experiment already done in the first.

Readouts

Mitochondrial translation output in the 2022 patient's fibroblasts

pathophysiology#Impaired Mitochondrial Protein Synthesis

Direction: DECREASED

Interpretation: Reduced incorporation into the thirteen mtDNA-encoded products would replicate the founding family's central finding in an independent genotype.

Would support

pathophysiology#Reduced 12S rRNA and Impaired Small Subunit Assembly pathophysiology#Impaired Mitochondrial Protein Synthesis

Supporting outcome

The compound-heterozygous cells show reduced MRPS7, a small-subunit assembly defect, reduced mitochondrial translation and a combined respiratory-chain deficiency, all corrected by wild-type MRPS7.

Refuting outcome

Mitoribosome assembly, translation and respiratory-chain activity are normal in the compound-heterozygous cells, which would leave the ovarian phenotype in that family unexplained by a mitoribosomal mechanism.

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Pathophysiology

10

Biallelic MRPS7 Variants

Two damaged copies of MRPS7. Three alleles are known across the two published families. The 2015 sisters are homozygous for c.550A>G, p.Met184Val, replacing a highly conserved methionine. The 2022 patient carries c.373A>T, p.(Lys125*), a nonsense allele, in trans with c.536G>A, p.(Arg179His); both were novel at the time of report and were called pathogenic on in-silico prediction rather than on a functional assay, which is a real limit on that family's molecular evidence.

MRPS7 hgnc:14499

Genetic context MRPS7 hgnc:14499 allele_type: a homozygous conserved-residue missense variant in one family, and a nonsense variant in trans with a missense variant in the other variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Zygosity differs between the two families - homozygous in the 2015 siblings, compound heterozygous in the 2022 patient - so no single zygosity value describes the entity and the slot is left unset rather than asserting one family's configuration for both.

LOSS_OF_FUNCTION rests on the 2015 family alone, where wild-type MRPS7 complementation restored respiratory-chain activity and 12S rRNA levels in patient fibroblasts. The 2022 alleles were not functionally tested; a nonsense allele at codon 125 of a 242-residue protein is a plausible null, but that is an inference and no protein or transcript measurement was reported for it.

Downstream

Destabilization of the uS7m Protein of the Mitoribosomal Small Subunit

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings."

The founding allele, its conservation argument and the families it was found in.

PMID:36421788 SUPPORT Human Clinical

"Both novel variants are predicted to be pathogenic via in-silico algorithms."

The basis on which the second family's alleles were called pathogenic - prediction, not function. Quoted because it is the limit this node's notes records.

Destabilization of the uS7m Protein of the Mitoribosomal Small Subunit

MRPS7 is a 12S ribosomal-RNA-binding protein of the small subunit of the mitochondrial ribosome and is required for that subunit's assembly. The mammalian mitoribosome is a 55S particle built from a 28S small subunit - 12S rRNA plus about thirty nuclear-encoded proteins - and a 39S large subunit, with the proteins arranged largely on the periphery around the catalytic RNA core. A missense change at a conserved residue in one of those thirty proteins is therefore a defect in the scaffold that holds the rRNA in place, not in a catalytic site. The general rule established across mitoribosomal-protein disease is that such variants reduce the steady-state level of the affected protein, and this entry follows that reading. No direct measurement of MRPS7 protein abundance in patient cells is reported in the sources cited here, so this node is an inference from the assembly and rRNA phenotypes below rather than a measured quantity.

MRPS7 hgnc:14499

12S rRNA binding GO:0070181

mitochondrial small ribosomal subunit GO:0005763

Downstream

Reduced 12S rRNA and Impaired Small Subunit Assembly

Show evidence (3 references)

PMID:25556185 SUPPORT Other

"MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit."

The protein's identity and its assembly role, which is what makes a point mutation in it a ribosome-assembly defect. Graded OTHER because the sentence states established background biology rather than a result of the study.

PMID:38855161 SUPPORT Other

"The mammalian 55S mitoribosome is composed of two subunits, a small 28S subunit (mt-SSU) which contains 12S rRNA and 30 nuclear-encoded mitochondrial ribosomal proteins (MRPs), and a large 39S subunit (mt-LSU), which includes 16S rRNA and 52 nuclear-encoded MRPs"

The composition of the particle MRPS7 belongs to. Graded OTHER because it is a review's structural synthesis rather than an experiment.

PMID:38855161 SUPPORT INDIRECT Other

"In the majority of these patients, the mutations result in a decrease in the steady-state levels of the affected protein and, as a consequence, the assembly of the ribosome is impaired and results in an overall reduction of protein synthesis."

The general mechanism across mitoribosomal-protein disease, which is the basis for this node. INDIRECT because it is stated for the class and not measured for MRPS7.

Reduced 12S rRNA and Impaired Small Subunit Assembly

12S rRNA transcript levels were reduced in patient fibroblasts and were restored to normal by exogenous wild-type MRPS7. The direction of that rescue is the informative part: the rRNA loss follows the protein defect rather than preceding it, so this is a failure to build and hold the small subunit together, not a transcriptional lesion in the mitochondrial genome.

mitochondrial small ribosomal subunit assembly GO:0180026 ↓ DECREASED

Experimental models

Lentiviral wild-type MRPS7 complementation of patient fibroblasts PRIMARY CELL CULTURE The same complementation restores 12S rRNA to normal levels, which is what establishes the direction of the relationship between the protein defect and the rRNA loss.

Downstream

Impaired Mitochondrial Protein Synthesis

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."

Both the rRNA deficit and its rescue, which together place the rRNA loss downstream of the protein defect.

Impaired Mitochondrial Protein Synthesis

Pulse labelling of mitochondrial translation products in patient fibroblasts showed impaired mitochondrial protein synthesis. This is the functional consequence of a defective small subunit and the step at which a single ribosomal-protein defect becomes a multi-complex disease: the mitoribosome makes only thirteen proteins, but they are distributed across complexes I, III, IV and V.

mitochondrial translation GO:0032543 ↓ DECREASED

Downstream

Combined Deficiency of Respiratory Chain Complexes I, III and IV

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts."

The direct measurement of the translation defect in patient cells.

Combined Deficiency of Respiratory Chain Complexes I, III and IV

Complexes I, III and IV were all deficient, and the deficiency was demonstrated in two tissues - cultured fibroblasts and liver. The *combined* pattern is diagnostically informative: it points to mitochondrial gene expression rather than to any single respiratory-chain gene, because every complex except complex II carries mtDNA-encoded subunits and complex II alone is entirely nuclear-encoded.

electron transport chain GO:0022900 ↓ DECREASED

Experimental models

Lentiviral wild-type MRPS7 complementation of patient fibroblasts PRIMARY CELL CULTURE Supplying wild-type MRPS7 to the patients' own cells restores respiratory-chain activity, which demonstrates that the MRPS7 variant rather than something else in that genome causes the combined deficiency.

Downstream

Decreased Activity of Mitochondrial Complex I

Decreased Activity of Mitochondrial Complex III

Decreased Activity of Mitochondrial Complex IV

Impaired Oxidative Phosphorylation

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

The three deficient complexes and the two tissues they were measured in.

PMID:25556185 SUPPORT In Vitro

"Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."

The complementation that ties the enzyme deficiency back to the genotype. Note the rescue is reported for complexes I and IV; complex III is not named among the rescued activities.

Impaired Oxidative Phosphorylation

With three of the four electron-transport complexes deficient, oxidative ATP synthesis falls. This is the bioenergetic endpoint that disease-specific mitochondrial lesions converge on, and the node conforms to the shared mitochondrial_dysfunction module at that point, as the sibling entry COXPD48 does. The module's central effector state pairs falling oxidative phosphorylation with rising reactive oxygen species. Only the first half is claimed here: no ROS measurement has been reported in an MRPS7 patient, and asserting the second half would import a claim from the module rather than from this disease. The consequence of the failing chain that these patients actually show is downstream - the cytosolic redox shift and the lactic acidemia, which are their own node.

oxidative phosphorylation GO:0006119 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Downstream

Lactic Acidemia

Bioenergetic Failure of Hepatocytes

Bioenergetic Failure of Renal Tubular Epithelium

Cochlear Bioenergetic Failure

Ovarian Follicular Depletion Marked INDIRECT_UNKNOWN_INTERMEDIATES because how a mitochondrial translation defect produces follicular loss is not established for this gene or, in general, for the mitoribosomal causes of Perrault syndrome. The edge records that the ovarian phenotype sits downstream of the OXPHOS defect, not a demonstrated pathway.

Show evidence (1 reference)

PMID:25556185 SUPPORT INDIRECT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

The co-occurrence of the enzyme deficiency and the lactic acidemia. INDIRECT because the redox mechanism this node names was not itself measured; what is reported is the lactate.

Bioenergetic Failure of Hepatocytes

Liver was one of the two tissues in which the combined respiratory-chain deficiency was measured, and hepatic failure was the clinical course in the more severely affected sister. Hepatocytes are oxidative and carry a high mitochondrial load, and hepatic involvement is a recurrent feature of mitochondrial translation defects. Why one sister with an identical homozygous genotype developed liver failure and the other did not is unexplained.

hepatocyte CL:0000182

Downstream

Hepatic Failure

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."

The hepatic involvement, attributed to one of the two siblings - which is what sets the frequency band on the phenotype below.

Bioenergetic Failure of Renal Tubular Epithelium

The proximal tubule is among the most mitochondria-dense epithelia in the body, and renal failure accompanied the hepatic failure in the same severely affected sister. No renal biopsy, tubular-function profile or respiratory-chain assay in kidney is reported, so the tubular localisation is inferred from the general biology rather than demonstrated here.

kidney epithelial cell CL:0002518

Downstream

Renal Insufficiency

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."

The renal involvement, in the same single sibling as the hepatic failure.

Cochlear Bioenergetic Failure

Sensorineural hearing loss is the one feature shared by all three published patients and is congenital in the two sisters. Cochlear hair cells and the stria vascularis maintain the endocochlear potential at a very high metabolic cost, which is the standing explanation for why hearing is disproportionately affected across mitochondrial disease generally and across mitoribosomal defects in particular. No cochlear tissue study exists for this gene, so the node asserts the vulnerability rather than a demonstrated mechanism.

auditory hair cell CL:0000202

Downstream

Sensorineural Hearing Impairment

Show evidence (1 reference)

PMID:38855161 SUPPORT INDIRECT Other

"The predominant clinical features include lactic acidosis, sensorineural hearing loss, hypertrophic cardiomyopathy and neurodevelopmental disabilities, nevertheless patients also present specific clinical features such as corpus callosum agenesis, Leigh syndrome, hypoglycemia or ovarian insufficiency."

Hearing loss as a predominant feature of mitoribosomal-protein disease as a class. INDIRECT because it establishes the pattern rather than the cochlear mechanism this node names.

Ovarian Follicular Depletion

Premature ovarian insufficiency is the phenotype that gave MRPS7 its second identity, as a Perrault syndrome gene. It appeared in the surviving 2015 sister - only after the report, and only once she reached reproductive age - and in the 2022 patient. Ovarian insufficiency recurs across the mitoribosomal and mitochondrial-translation genes, but the mechanism linking a translation defect to follicular loss is not established, and no ovarian histology or hormone-response study exists for MRPS7.

Downstream

Premature Ovarian Insufficiency

Show evidence (1 reference)

PMID:36421788 SUPPORT Human Clinical

"Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."

The ovarian phenotype in the surviving 2015 sister, recognised retrospectively, and its concordance with the 2022 patient.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Digestive 1

Hepatic Failure FREQUENT HP:0001399

1 of 3 published patients would fall in OCCASIONAL, but the relevant denominator is the two siblings for whom hepatic status is reported, giving 1 of 2 and the FREQUENT band. The 2022 report describes no liver phenotype for its own patient and is not counted either way.

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."

The hepatic failure, and its restriction to one of the two siblings.

PMID:36421788 SUPPORT Human Clinical

"The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."

The outcome of that hepatic and renal failure, reported later by the second group.

Ear 1

Sensorineural Hearing Impairment VERY_FREQUENT HP:0000407

3 of 3 published patients. VERY_FREQUENT rather than OBLIGATE: it is universal in the series, but a denominator of three cannot support an obligate claim. HP:0008527 (Congenital sensorineural hearing impairment) would fit the 2015 siblings and not the 2022 patient, so the parent term is bound and the congenital onset carried in preferred_term.

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

Congenital sensorineural deafness in both siblings of the first family.

PMID:36421788 SUPPORT Human Clinical

"Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease."

The hearing loss in the third patient, which makes the feature universal in the series.

Endocrine 1

Hashimoto Thyroiditis OCCASIONAL HP:0000872

1 of 3 published patients. Deliberately not wired into the pathograph: nothing connects an autoimmune thyroid disease to the OXPHOS defect in this entity, and drawing an edge would assert a mechanism that no source supports. Autoimmune thyroid disease is also common in the general female population, so a single co-occurrence is weak evidence of any relationship with the genotype.

Show evidence (1 reference)

PMID:36421788 SUPPORT Human Clinical

"Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease."

The thyroid finding in the third patient, in the same sentence as her two cardinal features.

Genitourinary 2

Renal Insufficiency FREQUENT HP:0000083

1 of 2 siblings, as for hepatic failure; the two organ failures were reported together.

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."

The renal failure, in one of the two siblings.

Premature Ovarian Insufficiency FREQUENT HP:0008209

2 of 3 published patients, which is the FREQUENT band. The denominator is distorted in a way worth stating: the third patient died in early adolescence, before a reproductive phenotype could be ascertained at all, so this is 2 of 2 among those who reached reproductive age. The phenotype is also sex-limited, and all three published patients are female.

Show evidence (2 references)

PMID:36421788 SUPPORT Human Clinical

"Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."

POI in the surviving 2015 sister and in the 2022 patient.

PMID:36421788 SUPPORT Human Clinical

"The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."

Why the third patient contributes no information about the ovarian phenotype - the ascertainment limit this phenotype's notes records.

Metabolism 1

Lactic Acidemia VERY_FREQUENT Increased circulating lactate concentration HP:0002151

2 of 2 patients in the 2015 family. The 2022 report does not mention lactate, so the denominator is two rather than three. Bound to the circulating-lactate term rather than HP:0003128 (Lactic acidosis), because the source says "lactic acidemia" - a raised lactate - and does not report acidosis.

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

The lactic acidemia in both siblings, stated together with the enzyme deficiency.

Cellular 3

Decreased Activity of Mitochondrial Complex I VERY_FREQUENT HP:0011923

Reported for the 2015 siblings, in whom the assay was performed; no respiratory-chain enzymology is reported for the 2022 patient. Denominator two.

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

Complex I named among the deficient complexes, with the tissues.

Decreased Activity of Mitochondrial Complex III VERY_FREQUENT HP:0011924

Reported for the 2015 siblings; denominator two, as for the other two complexes.

Show evidence (1 reference)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

Complex III named among the deficient complexes.

Decreased Activity of Mitochondrial Complex IV VERY_FREQUENT HP:0008347

Reported for the 2015 siblings; denominator two.

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."

Complex IV named among the deficient complexes.

PMID:25556185 SUPPORT In Vitro

"Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."

The rescue of complex IV activity, which is the functional confirmation for this measurement.

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Genetic Associations

1

MRPS7

Gene: MRPS7 hgnc:14499 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:25556185 SUPPORT Human Clinical

"Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure."

The gene-disease relationship as claimed by the report that established it.

PMID:25556185 SUPPORT In Vitro

"Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."

The complementation result that converts a variant association into a causal claim, and the only functional evidence in the entity.

PMID:36421788 SUPPORT Human Clinical

"This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome."

The second family, and the second identity it gave the gene. Cited here because independent replication is what the gene-disease relationship most needed, even though the disease label the authors use is not this entry's.

+ 1 more reference

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Medical Actions

1

Supportive care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

No disease-modifying therapy exists for COXPD34 and none has been trialled; the literature is three case descriptions with no treatment arm. Management is the supportive care used across mitochondrial disease and directed at the organs that fail - hearing rehabilitation, hepatic and renal support, and hormone replacement where premature ovarian insufficiency is present. None of that is specific to MRPS7, and none of it is reported for these patients in the sources cited here.

🔬

Diagnosis

1

Combined respiratory-chain deficiency followed by exome sequencing

The diagnostic logic in the founding family runs from the biochemistry to the gene. A *combined* deficiency of complexes I, III and IV - sparing complex II, the one complex with no mtDNA-encoded subunit - localises the lesion to mitochondrial gene expression, which narrows an otherwise unmanageable candidate list to the mitoribosome, the mitochondrial aminoacyl-tRNA synthetases, the translation factors and mtDNA maintenance. Whole-exome sequencing then names the gene. There is no MRPS7-specific biomarker and nothing that distinguishes this entity from any other mitochondrial translation defect short of sequencing. The second family reached the same gene from the opposite direction, through an exome performed for premature ovarian insufficiency. That is worth recording as a diagnostic route in its own right: a patient can arrive at this gene through a reproductive-endocrine presentation with no mitochondrial-disease workup at all.

Show evidence (2 references)

PMID:25556185 SUPPORT Human Clinical

"Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies."

The inference from a combined OXPHOS deficiency to the translation machinery, which is the diagnostic step.

PMID:36421788 SUPPORT Human Clinical

"The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome."

The clinical rule that took the second family to a genetic workup, and the reason that workup was framed as Perrault syndrome rather than as mitochondrial disease.

📈

Progression

2

Congenital and infantile presentation in the hepatorenal form

In the 2015 family the deafness is congenital and the lactic acidemia was present at presentation. The severe sister's hepatic and renal failure was progressive and ended in death in early adolescence; her sister survived to reproductive age. Fatal-outcome content is recorded here rather than as a phenotype, since the relevant HPO mortality terms sit outside the phenotype enum.

Show evidence (1 reference)

PMID:36421788 SUPPORT Human Clinical

"The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."

The age and cause of death in the severe sibling.

Reproductive-age presentation in the ovarian form

The ovarian phenotype cannot appear until reproductive age, which is why it was absent from the 2015 report and only recognised in the surviving sister later. This is a genuine natural-history feature of the entity rather than an artefact of reporting, and it means that any patient diagnosed in infancy has an unascertained reproductive phenotype - the reason the ovarian frequency band in this entry carries an explicit denominator caveat.

Show evidence (1 reference)

PMID:36421788 SUPPORT Human Clinical

"POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40."

The definition of the ovarian phenotype, which is what makes it unascertainable before reproductive age.

📊

Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Three patients in two families, reported in 2015 and 2022, and no further case found in a September 2026 PubMed and Europe PMC search on the gene symbol. No population estimate exists and none could be made: both families were ascertained through diagnostic exome sequencing, the first from a mitochondrial-disease phenotype and the second from a premature ovarian insufficiency phenotype. The prevalence_class is the numeric floor tier; no rate_per_100000 is given because none has been reported. One caveat on the count of three. The falcon deep-research report committed alongside this entry states, from the full text of the 2022 paper, that the second family also included a similarly affected sister whose genotype was not reported. The abstract - which is all that was retrievable into the reference cache - does not mention her, so that fourth individual could not be verified against a quotable source and is not counted in the denominators used throughout this entry. If she is real, every "of 3" figure below is a "of 4" with an ungenotyped member, which would not change any band.

Show evidence (1 reference)

PMID:36421788 SUPPORT Human Clinical

"Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."

The size of the literature as of the second report - one prior publication, in one sibship.

🧫

Experimental Models

1

Lentiviral wild-type MRPS7 complementation of patient fibroblasts PRIMARY_CELL_CULTURE

Patient fibroblasts from the 2015 family were complemented with wild-type MRPS7. Two independent readouts recovered: complex I and complex IV enzyme activities, and 12S rRNA transcript level. This is the only functional experiment in the entity, and it does two things at once - it establishes causation, and it orders the molecular events, since the rRNA deficit is corrected by supplying the protein.

Pathograph links

Combined Deficiency of Respiratory Chain Complexes I, III and IV rescues fidelity: high Supplying wild-type MRPS7 to the patients' own cells restores respiratory-chain activity, which demonstrates that the MRPS7 variant rather than something else in that genome causes the combined deficiency.

Limitations: A cultured fibroblast, so it says nothing about liver, kidney, cochlea or ovary - the four tissues that carry the clinical phenotype. The rescue is reported for complexes I and IV; complex III, although deficient, is not named among the rescued activities, and the source does not say whether it was assayed. Only the 2015 family was tested; the 2022 alleles have no functional data at all. Lentiviral overexpression is non-physiological in level and timing.

Readouts

Complex I and complex IV enzyme activities after wild-type MRPS7 expression

Direction: RESTORED

Interpretation: Both activities recover in complemented patient fibroblasts. The magnitude of recovery is not given in the source available here.

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."

The enzymatic readout of the rescue, naming the two complexes measured.

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."

Establishes that this cell system is informative for the enzyme-deficiency node it is linked to.

Reduced 12S rRNA and Impaired Small Subunit Assembly rescues fidelity: high The same complementation restores 12S rRNA to normal levels, which is what establishes the direction of the relationship between the protein defect and the rRNA loss.

Limitations: Transcript level is a proxy for subunit assembly rather than a measurement of it; no sucrose-gradient, blue-native or complexome profile of the mitoribosome in patient cells is reported, so the assembly claim in the node this links to is inferred from rRNA abundance and translation output rather than observed directly.

Readouts

12S rRNA transcript level after wild-type MRPS7 expression

Direction: RESTORED

Interpretation: 12S rRNA returns to normal levels when wild-type MRPS7 is supplied, placing the rRNA deficit downstream of the protein defect.

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."

The rRNA readout of the rescue.

Show evidence (1 reference)

PMID:25556185 SUPPORT In Vitro

"Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."

Establishes that this cell system is informative for the rRNA and assembly node.

{ }

Source YAML

click to show

name: Combined Oxidative Phosphorylation Deficiency 34
category: Mendelian
creation_date: "2026-09-09T00:00:00Z"
synonyms:
- COXPD34
- combined oxidative phosphorylation deficiency type 34
- syndromic sensorineural deafness due to combined oxidative phosphorylation defect
- syndromic sensorineural hearing loss due to COXPD
- MRPS7-related combined oxidative phosphorylation deficiency
- MRPS7 deficiency
disease_term:
  preferred_term: combined oxidative phosphorylation deficiency 34
  term:
    id: MONDO:0054741
    label: combined oxidative phosphorylation deficiency 34
description: >-
  COXPD34 is the combined oxidative phosphorylation deficiency caused by biallelic variants in
  MRPS7. It is one of the smallest entities in the numbered COXPD series: three patients in
  two families, reported in 2015 and 2022, and nothing since.

  MRPS7 encodes a protein of the small (28S) subunit of the mitochondrial ribosome, where it
  binds the 12S ribosomal RNA and is required for assembly of that subunit. The mitoribosome
  translates the thirteen mtDNA-encoded proteins, all of which are subunits of complexes I,
  III, IV and V, so a defect in it produces a *combined* respiratory-chain deficiency rather
  than the isolated single-complex defect seen when a nuclear subunit gene fails. That is what
  places this entity in the COXPD series rather than among the complex I deficiencies.

  The lesion was defined in two sisters homozygous for c.550A>G, p.Met184Val, a substitution
  at a highly conserved methionine. Their fibroblasts and liver showed combined deficiency of
  complexes I, III and IV; pulse labelling showed impaired mitochondrial protein synthesis; and
  12S rRNA transcript levels were reduced. Expressing wild-type MRPS7 in the patients'
  fibroblasts restored both complex I and complex IV activity and the 12S rRNA level - the
  complementation that establishes causation and, incidentally, shows that the 12S rRNA loss is
  downstream of the protein defect rather than a separate lesion.

  Clinically the two sisters shared congenital sensorineural deafness and lactic acidemia and
  then diverged sharply: one developed progressive hepatic and renal failure and died in early
  adolescence, while the other survived to be recognised, years later, as having premature
  ovarian insufficiency. That second phenotype is why the entity has a second identity. When a
  third patient was reported in 2022 - compound heterozygous for p.(Lys125*) and p.(Arg179His),
  with POI, sensorineural hearing loss and Hashimoto's disease - the authors framed the gene as
  a cause of syndromic POI and Perrault syndrome, not as a cause of COXPD34. dismech curates
  both readings: this entry covers the hepatorenal, lactic-acidemic presentation that OMIM
  617872 names, and `Perrault_Syndrome` carries MRPS7 as one of its causative genes. Neither is
  the whole gene, and the entry says so rather than annexing the other phenotype.

  The evidence base is thin and the entry is written to that. ClinGen's Mitochondrial Diseases
  expert panel classifies the MRPS7 gene-disease relationship as Limited, and OMIM's own
  gene-phenotype mapping for 617872 is flagged provisional. There is no animal model, no
  natural-history series, no prevalence estimate and no treatment evidence.
parents:
- Combined Oxidative Phosphorylation Deficiency
- Mitochondrial Disease
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian, mechanism-defined mitochondrial disorder, diagnosed and managed as an
      inherited disease rather than within a single organ-system Part.
  mechanistic_category:
  - classification_value: mitochondrial disease
  icimd_category:
  - classification_value: mitoribosome
    notes: >-
      MRPS7 is a structural protein of the mitoribosomal small subunit, so the lesion is in the
      mitochondrial translation apparatus itself rather than in any respiratory-chain subunit or
      assembly factor.
references:
- reference: PMID:25556185
  title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
- reference: PMID:36421788
  title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
- reference: PMID:38855161
  title: Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Both families are biallelic. The 2015 sisters are homozygous for a single missense allele;
    the 2022 patient is compound heterozygous for a nonsense and a missense allele. MRPS7 is
    nuclear-encoded and autosomal, so despite the mitochondrial phenotype this is a nuclear
    recessive disease with a 25 percent sibling recurrence risk and no maternal transmission.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings."
    explanation: Homozygosity for one allele in both affected siblings, which is the recessive segregation in the first family.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His)."
    explanation: >-
      The second family's biallelic configuration, which is compound heterozygous rather than
      homozygous - so the recessive claim does not rest on consanguinity alone.
pathophysiology:
- name: Biallelic MRPS7 Variants
  biological_scale: MOLECULAR
  description: >-
    Two damaged copies of MRPS7. Three alleles are known across the two published families. The
    2015 sisters are homozygous for c.550A>G, p.Met184Val, replacing a highly conserved
    methionine. The 2022 patient carries c.373A>T, p.(Lys125*), a nonsense allele, in trans with
    c.536G>A, p.(Arg179His); both were novel at the time of report and were called pathogenic on
    in-silico prediction rather than on a functional assay, which is a real limit on that
    family's molecular evidence.
  genes:
  - preferred_term: MRPS7
    term:
      id: hgnc:14499
      label: MRPS7
  genetic_context:
    genes:
    - preferred_term: MRPS7
      term:
        id: hgnc:14499
        label: MRPS7
    allele_type: a homozygous conserved-residue missense variant in one family, and a nonsense variant in trans with a missense variant in the other
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Zygosity differs between the two families - homozygous in the 2015 siblings, compound
      heterozygous in the 2022 patient - so no single zygosity value describes the entity and the
      slot is left unset rather than asserting one family's configuration for both.
    notes: >-
      LOSS_OF_FUNCTION rests on the 2015 family alone, where wild-type MRPS7 complementation
      restored respiratory-chain activity and 12S rRNA levels in patient fibroblasts. The 2022
      alleles were not functionally tested; a nonsense allele at codon 125 of a 242-residue
      protein is a plausible null, but that is an inference and no protein or transcript
      measurement was reported for it.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a homozygous mutation in the gene encoding mitochondrial ribosomal protein S7 (MRPS7), a c.550A>G transition that encodes a substitution of valine for a highly conserved methionine (p.Met184Val) in both affected siblings."
    explanation: The founding allele, its conservation argument and the families it was found in.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both novel variants are predicted to be pathogenic via in-silico algorithms."
    explanation: >-
      The basis on which the second family's alleles were called pathogenic - prediction, not
      function. Quoted because it is the limit this node's notes records.
  downstream:
  - target: Destabilization of the uS7m Protein of the Mitoribosomal Small Subunit
    causal_link_type: DIRECT
- name: Destabilization of the uS7m Protein of the Mitoribosomal Small Subunit
  biological_scale: MOLECULAR
  description: >-
    MRPS7 is a 12S ribosomal-RNA-binding protein of the small subunit of the mitochondrial
    ribosome and is required for that subunit's assembly. The mammalian mitoribosome is a 55S
    particle built from a 28S small subunit - 12S rRNA plus about thirty nuclear-encoded
    proteins - and a 39S large subunit, with the proteins arranged largely on the periphery
    around the catalytic RNA core. A missense change at a conserved residue in one of those
    thirty proteins is therefore a defect in the scaffold that holds the rRNA in place, not in
    a catalytic site.

    The general rule established across mitoribosomal-protein disease is that such variants
    reduce the steady-state level of the affected protein, and this entry follows that reading.
    No direct measurement of MRPS7 protein abundance in patient cells is reported in the sources
    cited here, so this node is an inference from the assembly and rRNA phenotypes below rather
    than a measured quantity.
  genes:
  - preferred_term: MRPS7
    term:
      id: hgnc:14499
      label: MRPS7
  cellular_components:
  - preferred_term: mitochondrial small ribosomal subunit
    term:
      id: GO:0005763
      label: mitochondrial small ribosomal subunit
  molecular_functions:
  - preferred_term: 12S rRNA binding
    term:
      id: GO:0070181
      label: small ribosomal subunit rRNA binding
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MRPS7 is a 12S ribosomal RNA-binding subunit of the small mitochondrial ribosomal subunit, and is required for the assembly of the small ribosomal subunit."
    explanation: >-
      The protein's identity and its assembly role, which is what makes a point mutation in it a
      ribosome-assembly defect. Graded OTHER because the sentence states established background
      biology rather than a result of the study.
  - reference: PMID:38855161
    reference_title: Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mammalian 55S mitoribosome is composed of two subunits, a small 28S subunit (mt-SSU) which contains 12S rRNA and 30 nuclear-encoded mitochondrial ribosomal proteins (MRPs), and a large 39S subunit (mt-LSU), which includes 16S rRNA and 52 nuclear-encoded MRPs"
    explanation: >-
      The composition of the particle MRPS7 belongs to. Graded OTHER because it is a review's
      structural synthesis rather than an experiment.
  - reference: PMID:38855161
    reference_title: Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "In the majority of these patients, the mutations result in a decrease in the steady-state levels of the affected protein and, as a consequence, the assembly of the ribosome is impaired and results in an overall reduction of protein synthesis."
    explanation: >-
      The general mechanism across mitoribosomal-protein disease, which is the basis for this
      node. INDIRECT because it is stated for the class and not measured for MRPS7.
  downstream:
  - target: Reduced 12S rRNA and Impaired Small Subunit Assembly
    causal_link_type: DIRECT
- name: Reduced 12S rRNA and Impaired Small Subunit Assembly
  biological_scale: MOLECULAR
  description: >-
    12S rRNA transcript levels were reduced in patient fibroblasts and were restored to normal by
    exogenous wild-type MRPS7. The direction of that rescue is the informative part: the rRNA
    loss follows the protein defect rather than preceding it, so this is a failure to build and
    hold the small subunit together, not a transcriptional lesion in the mitochondrial genome.
  biological_processes:
  - preferred_term: mitochondrial small ribosomal subunit assembly
    modifier: DECREASED
    term:
      id: GO:0180026
      label: mitochondrial small ribosomal subunit assembly
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."
    explanation: >-
      Both the rRNA deficit and its rescue, which together place the rRNA loss downstream of the
      protein defect.
  downstream:
  - target: Impaired Mitochondrial Protein Synthesis
    causal_link_type: DIRECT
- name: Impaired Mitochondrial Protein Synthesis
  biological_scale: CELLULAR
  description: >-
    Pulse labelling of mitochondrial translation products in patient fibroblasts showed impaired
    mitochondrial protein synthesis. This is the functional consequence of a defective small
    subunit and the step at which a single ribosomal-protein defect becomes a multi-complex
    disease: the mitoribosome makes only thirteen proteins, but they are distributed across
    complexes I, III, IV and V.
  biological_processes:
  - preferred_term: mitochondrial translation
    modifier: DECREASED
    term:
      id: GO:0032543
      label: mitochondrial translation
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts."
    explanation: The direct measurement of the translation defect in patient cells.
  downstream:
  - target: Combined Deficiency of Respiratory Chain Complexes I, III and IV
    causal_link_type: DIRECT
- name: Combined Deficiency of Respiratory Chain Complexes I, III and IV
  biological_scale: CELLULAR
  description: >-
    Complexes I, III and IV were all deficient, and the deficiency was demonstrated in two
    tissues - cultured fibroblasts and liver. The *combined* pattern is diagnostically
    informative: it points to mitochondrial gene expression rather than to any single
    respiratory-chain gene, because every complex except complex II carries mtDNA-encoded
    subunits and complex II alone is entirely nuclear-encoded.
  biological_processes:
  - preferred_term: electron transport chain
    modifier: DECREASED
    term:
      id: GO:0022900
      label: electron transport chain
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: The three deficient complexes and the two tissues they were measured in.
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."
    explanation: >-
      The complementation that ties the enzyme deficiency back to the genotype. Note the rescue is
      reported for complexes I and IV; complex III is not named among the rescued activities.
  downstream:
  - target: Decreased Activity of Mitochondrial Complex I
    causal_link_type: DIRECT
  - target: Decreased Activity of Mitochondrial Complex III
    causal_link_type: DIRECT
  - target: Decreased Activity of Mitochondrial Complex IV
    causal_link_type: DIRECT
  - target: Impaired Oxidative Phosphorylation
    causal_link_type: DIRECT
- name: Impaired Oxidative Phosphorylation
  biological_scale: CELLULAR
  conforms_to: "mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress"
  description: >-
    With three of the four electron-transport complexes deficient, oxidative ATP synthesis falls.
    This is the bioenergetic endpoint that disease-specific mitochondrial lesions converge on,
    and the node conforms to the shared mitochondrial_dysfunction module at that point, as the
    sibling entry COXPD48 does.

    The module's central effector state pairs falling oxidative phosphorylation with rising
    reactive oxygen species. Only the first half is claimed here: no ROS measurement has been
    reported in an MRPS7 patient, and asserting the second half would import a claim from the
    module rather than from this disease.

    The consequence of the failing chain that these patients actually show is downstream - the
    cytosolic redox shift and the lactic acidemia, which are their own node.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: >-
      The co-occurrence of the enzyme deficiency and the lactic acidemia. INDIRECT because the
      redox mechanism this node names was not itself measured; what is reported is the lactate.
  downstream:
  - target: Lactic Acidemia
    causal_link_type: DIRECT
  - target: Bioenergetic Failure of Hepatocytes
    causal_link_type: DIRECT
  - target: Bioenergetic Failure of Renal Tubular Epithelium
    causal_link_type: DIRECT
  - target: Cochlear Bioenergetic Failure
    causal_link_type: DIRECT
  - target: Ovarian Follicular Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Marked INDIRECT_UNKNOWN_INTERMEDIATES because how a mitochondrial translation defect
      produces follicular loss is not established for this gene or, in general, for the
      mitoribosomal causes of Perrault syndrome. The edge records that the ovarian phenotype sits
      downstream of the OXPHOS defect, not a demonstrated pathway.
- name: Bioenergetic Failure of Hepatocytes
  biological_scale: TISSUE
  description: >-
    Liver was one of the two tissues in which the combined respiratory-chain deficiency was
    measured, and hepatic failure was the clinical course in the more severely affected sister.
    Hepatocytes are oxidative and carry a high mitochondrial load, and hepatic involvement is a
    recurrent feature of mitochondrial translation defects. Why one sister with an identical
    homozygous genotype developed liver failure and the other did not is unexplained.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."
    explanation: >-
      The hepatic involvement, attributed to one of the two siblings - which is what sets the
      frequency band on the phenotype below.
  downstream:
  - target: Hepatic Failure
    causal_link_type: DIRECT
- name: Bioenergetic Failure of Renal Tubular Epithelium
  biological_scale: TISSUE
  description: >-
    The proximal tubule is among the most mitochondria-dense epithelia in the body, and renal
    failure accompanied the hepatic failure in the same severely affected sister. No renal
    biopsy, tubular-function profile or respiratory-chain assay in kidney is reported, so the
    tubular localisation is inferred from the general biology rather than demonstrated here.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."
    explanation: The renal involvement, in the same single sibling as the hepatic failure.
  downstream:
  - target: Renal Insufficiency
    causal_link_type: DIRECT
- name: Cochlear Bioenergetic Failure
  biological_scale: TISSUE
  description: >-
    Sensorineural hearing loss is the one feature shared by all three published patients and is
    congenital in the two sisters. Cochlear hair cells and the stria vascularis maintain the
    endocochlear potential at a very high metabolic cost, which is the standing explanation for
    why hearing is disproportionately affected across mitochondrial disease generally and across
    mitoribosomal defects in particular. No cochlear tissue study exists for this gene, so the
    node asserts the vulnerability rather than a demonstrated mechanism.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  evidence:
  - reference: PMID:38855161
    reference_title: Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "The predominant clinical features include lactic acidosis, sensorineural hearing loss, hypertrophic cardiomyopathy and neurodevelopmental disabilities, nevertheless patients also present specific clinical features such as corpus callosum agenesis, Leigh syndrome, hypoglycemia or ovarian insufficiency."
    explanation: >-
      Hearing loss as a predominant feature of mitoribosomal-protein disease as a class. INDIRECT
      because it establishes the pattern rather than the cochlear mechanism this node names.
  downstream:
  - target: Sensorineural Hearing Impairment
    causal_link_type: DIRECT
- name: Ovarian Follicular Depletion
  biological_scale: TISSUE
  description: >-
    Premature ovarian insufficiency is the phenotype that gave MRPS7 its second identity, as a
    Perrault syndrome gene. It appeared in the surviving 2015 sister - only after the report, and
    only once she reached reproductive age - and in the 2022 patient. Ovarian insufficiency
    recurs across the mitoribosomal and mitochondrial-translation genes, but the mechanism
    linking a translation defect to follicular loss is not established, and no ovarian histology
    or hormone-response study exists for MRPS7.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."
    explanation: >-
      The ovarian phenotype in the surviving 2015 sister, recognised retrospectively, and its
      concordance with the 2022 patient.
  downstream:
  - target: Premature Ovarian Insufficiency
    causal_link_type: DIRECT
phenotypes:
- name: Sensorineural Hearing Impairment
  category: Nervous System
  description: >-
    The only feature present in all three published patients. It is congenital in the two 2015
    sisters; in the 2022 patient the hearing loss is reported without an age of onset, which is
    why this entry binds the general sensorineural term rather than the congenital one.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sensorineural hearing loss, congenital in the two reported siblings
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    3 of 3 published patients. VERY_FREQUENT rather than OBLIGATE: it is universal in the series,
    but a denominator of three cannot support an obligate claim. HP:0008527 (Congenital
    sensorineural hearing impairment) would fit the 2015 siblings and not the 2022 patient, so the
    parent term is bound and the congenital onset carried in preferred_term.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: Congenital sensorineural deafness in both siblings of the first family.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease."
    explanation: The hearing loss in the third patient, which makes the feature universal in the series.
- name: Lactic Acidemia
  category: Metabolism
  description: >-
    Raised blood lactate, present in both 2015 siblings alongside the deafness. No numerical
    values are given in the source available here, and lactate is not reported for the 2022
    patient.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lactic acidemia
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  notes: >-
    2 of 2 patients in the 2015 family. The 2022 report does not mention lactate, so the
    denominator is two rather than three. Bound to the circulating-lactate term rather than
    HP:0003128 (Lactic acidosis), because the source says "lactic acidemia" - a raised lactate -
    and does not report acidosis.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: The lactic acidemia in both siblings, stated together with the enzyme deficiency.
- name: Decreased Activity of Mitochondrial Complex I
  category: Metabolism
  description: >-
    Complex I deficiency in fibroblasts and liver, part of the combined pattern that defines the
    entity, and one of the two activities restored by wild-type MRPS7 complementation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex I
    term:
      id: HP:0011923
      label: Decreased activity of mitochondrial complex I
  notes: >-
    Reported for the 2015 siblings, in whom the assay was performed; no respiratory-chain
    enzymology is reported for the 2022 patient. Denominator two.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: Complex I named among the deficient complexes, with the tissues.
- name: Decreased Activity of Mitochondrial Complex III
  category: Metabolism
  description: >-
    Complex III deficiency in fibroblasts and liver. Unlike complexes I and IV, complex III
    activity is not named among the activities restored by wild-type MRPS7 in the complementation
    experiment; whether it was measured and not rescued, or simply not measured, is not stated.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex III
    term:
      id: HP:0011924
      label: Decreased activity of mitochondrial complex III
  notes: Reported for the 2015 siblings; denominator two, as for the other two complexes.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: Complex III named among the deficient complexes.
- name: Decreased Activity of Mitochondrial Complex IV
  category: Metabolism
  description: >-
    Complex IV deficiency in fibroblasts and liver, and the second of the two activities restored
    by wild-type MRPS7 complementation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex IV
    term:
      id: HP:0008347
      label: Decreased activity of mitochondrial complex IV
  notes: Reported for the 2015 siblings; denominator two.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report siblings with congenital sensorineural deafness and lactic acidemia in association with combined respiratory chain (RC) deficiencies of complexes I, III and IV observed in fibroblasts and liver."
    explanation: Complex IV named among the deficient complexes.
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."
    explanation: The rescue of complex IV activity, which is the functional confirmation for this measurement.
- name: Hepatic Failure
  category: Gastrointestinal
  description: >-
    Progressive hepatic failure in the more severely affected of the two 2015 sisters. She died in
    early adolescence of liver and renal failure. Her sister, homozygous for the same allele, had
    no reported liver disease.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  notes: >-
    1 of 3 published patients would fall in OCCASIONAL, but the relevant denominator is the two
    siblings for whom hepatic status is reported, giving 1 of 2 and the FREQUENT band. The 2022
    report describes no liver phenotype for its own patient and is not counted either way.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."
    explanation: The hepatic failure, and its restriction to one of the two siblings.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."
    explanation: The outcome of that hepatic and renal failure, reported later by the second group.
- name: Renal Insufficiency
  category: Renal
  description: >-
    Progressive renal failure in the same severely affected sister, contributing with the liver
    failure to her death in early adolescence. No description of the renal lesion is given.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive renal failure
    term:
      id: HP:0000083
      label: Renal insufficiency
  notes: 1 of 2 siblings, as for hepatic failure; the two organ failures were reported together.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the siblings had a more severe phenotype showing progressive hepatic and renal failure."
    explanation: The renal failure, in one of the two siblings.
- name: Premature Ovarian Insufficiency
  category: Endocrine
  description: >-
    Premature ovarian insufficiency in the surviving 2015 sister - recognised only after the
    original report, once she reached reproductive age - and in the 2022 patient. The
    co-occurrence with sensorineural hearing loss is what makes the presentation Perrault
    syndrome, and is why MRPS7 is also curated as a causative gene in the `Perrault_Syndrome`
    entry.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  notes: >-
    2 of 3 published patients, which is the FREQUENT band. The denominator is distorted in a way
    worth stating: the third patient died in early adolescence, before a reproductive phenotype
    could be ascertained at all, so this is 2 of 2 among those who reached reproductive age. The
    phenotype is also sex-limited, and all three published patients are female.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."
    explanation: POI in the surviving 2015 sister and in the 2022 patient.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."
    explanation: >-
      Why the third patient contributes no information about the ovarian phenotype - the
      ascertainment limit this phenotype's notes records.
- name: Hashimoto Thyroiditis
  category: Endocrine
  description: >-
    Autoimmune thyroiditis in the 2022 patient, reported alongside her POI and hearing loss. It is
    a single observation and no mechanistic link to mitochondrial translation is proposed by the
    authors or asserted here.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  notes: >-
    1 of 3 published patients. Deliberately not wired into the pathograph: nothing connects an
    autoimmune thyroid disease to the OXPHOS defect in this entity, and drawing an edge would
    assert a mechanism that no source supports. Autoimmune thyroid disease is also common in the
    general female population, so a single co-occurrence is weak evidence of any relationship
    with the genotype.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease."
    explanation: The thyroid finding in the third patient, in the same sentence as her two cardinal features.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Three patients in two families, reported in 2015 and 2022, and no further case found in a
    September 2026 PubMed and Europe PMC search on the gene symbol. No population estimate exists
    and none could be made: both families were ascertained through diagnostic exome sequencing,
    the first from a mitochondrial-disease phenotype and the second from a premature ovarian
    insufficiency phenotype. The prevalence_class is the numeric floor tier; no rate_per_100000 is
    given because none has been reported.

    One caveat on the count of three. The falcon deep-research report committed alongside this
    entry states, from the full text of the 2022 paper, that the second family also included a
    similarly affected sister whose genotype was not reported. The abstract - which is all that
    was retrievable into the reference cache - does not mention her, so that fourth individual
    could not be verified against a quotable source and is not counted in the denominators used
    throughout this entry. If she is real, every "of 3" figure below is a "of 4" with an
    ungenotyped member, which would not change any band.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype."
    explanation: >-
      The size of the literature as of the second report - one prior publication, in one sibship.
progression:
- phase: Congenital and infantile presentation in the hepatorenal form
  notes: >-
    In the 2015 family the deafness is congenital and the lactic acidemia was present at
    presentation. The severe sister's hepatic and renal failure was progressive and ended in death
    in early adolescence; her sister survived to reproductive age. Fatal-outcome content is
    recorded here rather than as a phenotype, since the relevant HPO mortality terms sit outside
    the phenotype enum.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known."
    explanation: The age and cause of death in the severe sibling.
- phase: Reproductive-age presentation in the ovarian form
  notes: >-
    The ovarian phenotype cannot appear until reproductive age, which is why it was absent from the
    2015 report and only recognised in the surviving sister later. This is a genuine natural-history
    feature of the entity rather than an artefact of reporting, and it means that any patient
    diagnosed in infancy has an unascertained reproductive phenotype - the reason the ovarian
    frequency band in this entry carries an explicit denominator caveat.
  evidence:
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40."
    explanation: >-
      The definition of the ovarian phenotype, which is what makes it unascertainable before
      reproductive age.
genetic:
- name: MRPS7
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: MRPS7
    term:
      id: hgnc:14499
      label: MRPS7
  notes: >-
    MRPS7 encodes mitochondrial ribosomal protein S7, a 12S rRNA-binding protein of the small
    subunit of the mitoribosome, designated uS7m in the standardised mitoribosome nomenclature -
    the "u" prefix marking it as one of the subunits conserved from the bacterial ribosome rather
    than a mitochondria-specific addition.

    Gene identity, and how it was established. Neither MONDO nor the curation stub for this
    disease records a causal gene. The gene was resolved from the OMIM identifier: MONDO:0054741
    carries skos:exactMatch to OMIM:617872, and NCBI's mim2gene_medgen table maps MIM 617872 to
    Gene ID 51081, which is MRPS7 (hgnc:14499). The literature is consistent with that mapping -
    the 2015 report's title names MRPS7 and describes exactly the phenotype OMIM 617872 carries.

    How strong the relationship is. ClinGen's Mitochondrial Diseases Gene Curation Expert Panel
    classified MRPS7 against mitochondrial disease as **Limited** on 17 June 2024, and NCBI's
    mim2gene_medgen record for MIM 617872 carries the comment `question`, OMIM's marker for a
    provisional gene-phenotype relationship. Two independent resources therefore agree that this
    is a weakly established entity. Neither is cited as an evidence item: the ClinGen assertion is
    absent from the ClinGen snapshot this repository has pinned, and repinning that snapshot is a
    separate change from curating a disease. Both facts were read directly from the respective
    downloads, and the ClinGen row can be cited here once the pin is refreshed.

    Two traps for anyone extending this entry from the gene rather than from the disease. First,
    MRPS7 has a large and entirely unrelated cancer literature - it appears in prognostic gene
    signatures and, most substantially, as a driver of cisplatin resistance in nasopharyngeal
    carcinoma through beta-catenin stabilisation. None of that concerns this disease. Second, the
    gene is genuinely pleiotropic in dismech's own terms: the same biallelic variants underlie
    both this entity and the Perrault-syndrome presentation curated in `Perrault_Syndrome`, and
    the two entries deliberately overlap on the gene while differing on the phenotype they model.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data demonstrate the pathogenicity of the identified MRPS7 mutation as a novel cause of mitochondrial RC dysfunction, congenital sensorineural deafness and progressive hepatic and renal failure."
    explanation: The gene-disease relationship as claimed by the report that established it.
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."
    explanation: >-
      The complementation result that converts a variant association into a causal claim, and the
      only functional evidence in the entity.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome."
    explanation: >-
      The second family, and the second identity it gave the gene. Cited here because independent
      replication is what the gene-disease relationship most needed, even though the disease label
      the authors use is not this entry's.
  - reference: PMID:38855161
    reference_title: Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "To date, mutations in genes MRPS2, MRPS7, MRPS9, MRPS14, MRPS16, MRPS22, MRPS23, MRPS25, MRPS28, MRPS34 and MRPS39, which encode mt-SSU subunits, and genes MRPL3, MRPL12, MRPL24, MRPL44 and MRPL50 which encode mt-LSU subunits have been linked to mitochondrial disorders"
    explanation: >-
      MRPS7 placed within the set of mitoribosomal-protein disease genes. Quoted as the flattened
      gene list because that is where the statement sits in the source. Graded OTHER because a
      review's enumeration is an expert synthesis rather than a study.
diagnosis:
- name: Combined respiratory-chain deficiency followed by exome sequencing
  description: >-
    The diagnostic logic in the founding family runs from the biochemistry to the gene. A
    *combined* deficiency of complexes I, III and IV - sparing complex II, the one complex with no
    mtDNA-encoded subunit - localises the lesion to mitochondrial gene expression, which narrows
    an otherwise unmanageable candidate list to the mitoribosome, the mitochondrial
    aminoacyl-tRNA synthetases, the translation factors and mtDNA maintenance. Whole-exome
    sequencing then names the gene. There is no MRPS7-specific biomarker and nothing that
    distinguishes this entity from any other mitochondrial translation defect short of sequencing.

    The second family reached the same gene from the opposite direction, through an exome
    performed for premature ovarian insufficiency. That is worth recording as a diagnostic route
    in its own right: a patient can arrive at this gene through a reproductive-endocrine
    presentation with no mitochondrial-disease workup at all.
  evidence:
  - reference: PMID:25556185
    reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional defects of the mitochondrial translation machinery, as a result of mutations in nuclear-encoded genes, have been associated with combined oxidative phosphorylation (OXPHOS) deficiencies."
    explanation: The inference from a combined OXPHOS deficiency to the translation machinery, which is the diagnostic step.
  - reference: PMID:36421788
    reference_title: "Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome."
    explanation: >-
      The clinical rule that took the second family to a genetic workup, and the reason that
      workup was framed as Perrault syndrome rather than as mitochondrial disease.
experimental_models:
- name: Lentiviral wild-type MRPS7 complementation of patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Patient fibroblasts from the 2015 family were complemented with wild-type MRPS7. Two
    independent readouts recovered: complex I and complex IV enzyme activities, and 12S rRNA
    transcript level. This is the only functional experiment in the entity, and it does two things
    at once - it establishes causation, and it orders the molecular events, since the rRNA deficit
    is corrected by supplying the protein.
  modeled_mechanisms:
  - target: Combined Deficiency of Respiratory Chain Complexes I, III and IV
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      Supplying wild-type MRPS7 to the patients' own cells restores respiratory-chain activity,
      which demonstrates that the MRPS7 variant rather than something else in that genome causes
      the combined deficiency.
    limitations: >-
      A cultured fibroblast, so it says nothing about liver, kidney, cochlea or ovary - the four
      tissues that carry the clinical phenotype. The rescue is reported for complexes I and IV;
      complex III, although deficient, is not named among the rescued activities, and the source
      does not say whether it was assayed. Only the 2015 family was tested; the 2022 alleles have
      no functional data at all. Lentiviral overexpression is non-physiological in level and
      timing.
    readouts:
    - name: Complex I and complex IV enzyme activities after wild-type MRPS7 expression
      target: Combined Deficiency of Respiratory Chain Complexes I, III and IV
      direction: RESTORED
      interpretation: >-
        Both activities recover in complemented patient fibroblasts. The magnitude of recovery is
        not given in the source available here.
      evidence:
      - reference: PMID:25556185
        reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."
        explanation: The enzymatic readout of the rescue, naming the two complexes measured.
    evidence:
    - reference: PMID:25556185
      reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Exogenous expression of wild-type MRPS7 in patient fibroblasts rescued complexes I and IV activities, demonstrating the deleterious effect of the mutation on RC function."
      explanation: Establishes that this cell system is informative for the enzyme-deficiency node it is linked to.
  - target: Reduced 12S rRNA and Impaired Small Subunit Assembly
    relationship: RESCUES
    fidelity: HIGH
    description: >-
      The same complementation restores 12S rRNA to normal levels, which is what establishes the
      direction of the relationship between the protein defect and the rRNA loss.
    limitations: >-
      Transcript level is a proxy for subunit assembly rather than a measurement of it; no
      sucrose-gradient, blue-native or complexome profile of the mitoribosome in patient cells is
      reported, so the assembly claim in the node this links to is inferred from rRNA abundance
      and translation output rather than observed directly.
    readouts:
    - name: 12S rRNA transcript level after wild-type MRPS7 expression
      target: Reduced 12S rRNA and Impaired Small Subunit Assembly
      direction: RESTORED
      interpretation: >-
        12S rRNA returns to normal levels when wild-type MRPS7 is supplied, placing the rRNA
        deficit downstream of the protein defect.
      evidence:
      - reference: PMID:25556185
        reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."
        explanation: The rRNA readout of the rescue.
    evidence:
    - reference: PMID:25556185
      reference_title: "Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Moreover, reduced 12S rRNA transcript levels observed in the patient's fibroblasts were also restored to normal levels by exogenous expression of wild-type MRPS7."
      explanation: Establishes that this cell system is informative for the rRNA and assembly node.
treatments:
- name: Supportive care
  description: >-
    No disease-modifying therapy exists for COXPD34 and none has been trialled; the literature is
    three case descriptions with no treatment arm. Management is the supportive care used across
    mitochondrial disease and directed at the organs that fail - hearing rehabilitation, hepatic
    and renal support, and hormone replacement where premature ovarian insufficiency is present.
    None of that is specific to MRPS7, and none of it is reported for these patients in the
    sources cited here.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  notes: >-
    Recorded with no evidence block and no target_mechanisms link, deliberately. There is no
    MRPS7-specific treatment publication to cite, an evidence item requires an exact quote
    supporting the specific claim, and asserting a mechanism link would claim an effect on the
    pathograph that nothing demonstrates.
discussions:
- discussion_id: coxpd34_two_entities_one_gene
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - disease#Combined Oxidative Phosphorylation Deficiency 34
  - phenotypes#Premature Ovarian Insufficiency
  prompt: >-
    Is COXPD34 a separate entity from MRPS7-related Perrault syndrome, or are they one disease
    ascertained at two ages?
  rationale: >-
    The three published MRPS7 patients are all female, all have sensorineural hearing loss, and
    the two who reached reproductive age both have premature ovarian insufficiency. That is
    Perrault syndrome in two of three. What separates the OMIM 617872 phenotype is the hepatorenal
    failure of the severely affected sister - and she died before her reproductive phenotype could
    be known, so nobody can say whether she would also have had POI.

    Read one way, MRPS7 causes a single disease whose severe end kills in adolescence and whose
    mild end presents to a fertility clinic, and the two names are an artefact of which specialist
    saw the patient. Read the other way, the hepatorenal course is a genuinely distinct
    presentation deserving its own entity. dismech currently curates both readings - this entry
    and the MRPS7 gene record in `Perrault_Syndrome` - which is honest about the uncertainty but
    means the same three patients appear in two places. Three patients is not enough to settle it;
    a fourth family, particularly one with a male sibling or with a liver phenotype ascertained
    after puberty, would be.
- discussion_id: coxpd34_limited_gene_disease_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic MRPS7 Variants
  prompt: >-
    Do the 2022 MRPS7 alleles cause a mitoribosomal defect, or are they only predicted to?
  rationale: >-
    ClinGen classifies MRPS7 against mitochondrial disease as Limited, and OMIM flags the
    gene-phenotype mapping as provisional. The reason is visible in the two reports: all of the
    functional evidence - impaired translation, reduced 12S rRNA, complementation rescue - comes
    from a single family homozygous for one missense allele. The second family's nonsense and
    missense alleles were called pathogenic on in-silico prediction alone, with no protein,
    transcript, assembly or respiratory-chain measurement. A single functional study of the
    p.(Lys125*) and p.(Arg179His) alleles would move this relationship materially, and is the
    cheapest available way to do so.
  proposed_experiments:
  - experiment_id: exp_coxpd34_second_family_function
    name: Functional characterisation of the 2022 MRPS7 alleles
    description: >-
      Measure MRPS7 protein and transcript abundance, mitoribosomal small-subunit assembly by
      sucrose-gradient or complexome profiling, mitochondrial translation by pulse labelling, and
      respiratory-chain enzyme activities in fibroblasts from the compound-heterozygous 2022
      patient, with wild-type MRPS7 complementation as the control - reproducing in that family
      the experiment already done in the first.
    would_support:
    - pathophysiology#Reduced 12S rRNA and Impaired Small Subunit Assembly
    - pathophysiology#Impaired Mitochondrial Protein Synthesis
    supporting_outcome:
    - >-
      The compound-heterozygous cells show reduced MRPS7, a small-subunit assembly defect, reduced
      mitochondrial translation and a combined respiratory-chain deficiency, all corrected by
      wild-type MRPS7.
    refuting_outcome:
    - >-
      Mitoribosome assembly, translation and respiratory-chain activity are normal in the
      compound-heterozygous cells, which would leave the ovarian phenotype in that family
      unexplained by a mitoribosomal mechanism.
    readouts:
    - name: Mitochondrial translation output in the 2022 patient's fibroblasts
      target: pathophysiology#Impaired Mitochondrial Protein Synthesis
      direction: DECREASED
      interpretation: >-
        Reduced incorporation into the thirteen mtDNA-encoded products would replicate the founding
        family's central finding in an independent genotype.
notes: >-
  Scope and shape. entry_type DISEASE, standalone, consistent with how dismech curates the rest of
  the numbered COXPD series (defects 4, 7, 13, 21, 23, 26, 30 and deficiencies 42, 48, 51 are all
  separate files). The stub is deleted because MONDO:0054741 is now bound by this entry's
  disease_term.

  Relationship with Perrault_Syndrome. This is the one thing a reviewer should look at hardest.
  MRPS7 is already curated as a causative gene in `Perrault_Syndrome`, on the strength of the same
  two publications, and that entry's own notes describe exactly this pattern - a pleiotropic gene
  whose other phenotype is curated separately and cross-referenced rather than imported. This entry
  follows the same convention in the opposite direction: it models the hepatorenal, lactic-acidemic
  presentation that OMIM 617872 names, records the ovarian phenotype because two of the three
  published patients have it, and points at `Perrault_Syndrome` rather than re-curating the
  Perrault phenotype. An OPEN_QUESTION discussion records that the two may be one disease seen at
  two ages, which three patients cannot settle.

  Gene identity. Neither MONDO nor the stub records a causal gene for MONDO:0054741. MRPS7
  (hgnc:14499) was resolved through the OMIM exact match - MONDO:0054741 to OMIM:617872 to NCBI
  Gene 51081 in mim2gene_medgen - and is corroborated by the founding paper's own title. Note
  hgnc:14499 and not hgnc:14508, which is MRPS22, a different mitoribosomal small-subunit gene
  curated elsewhere in this repository.

  ClinGen and OMIM are not cited as evidence items, and that is deliberate. ClinGen's June 2024
  MRPS7 assertion (Limited) is absent from the ClinGen gene-validity snapshot pinned in
  `data/clingen/MANIFEST.yaml`, and building a cache file from a newer, unpinned download would
  commit an artifact that cannot be reproduced from the pin - a manifest repin is its own change,
  not part of a curation PR. Both the ClinGen classification and the OMIM provisional flag are
  recorded in the `genetic` notes with their sources named, and both were read directly from the
  respective downloads rather than inferred.

  Module conformance and node naming. The Impaired Oxidative Phosphorylation node declares
  `conforms_to: mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress`, following
  the sibling entry COXPD48, which conforms its equivalent node to the same target. Only the
  oxidative-phosphorylation half of that module node's effector state is claimed: the module also
  pairs it with rising reactive oxygen species, and no ROS measurement has been reported in an
  MRPS7 patient.

  One node name still reads as a bundle and is kept deliberately: "Reduced 12S rRNA and Impaired
  Small Subunit Assembly". The two are one claim rather than two - 12S rRNA transcript level is
  the measurement that was made, and small-subunit assembly is what it stands for - and the node
  and the model link both say so, including that no gradient or complexome profile of the
  mitoribosome in patient cells exists. Naming it for the assembly alone would assert a
  measurement that was not made; naming it for the rRNA alone would lose the mechanism.

  Two corrections this entry took from its deep-research report. The report is on the right
  disease - MRPS7 is mentioned 45 times and dominates its gene counts - and it independently
  resolved the same gene and OMIM numbers this entry did. It corrected the standardised
  mitoribosome name for the protein, which is uS7m rather than mS7, and it reports from the 2022
  paper's full text an additional similarly affected sister whose genotype was not given. The
  first correction is applied; the second is recorded in the prevalence notes as an unverifiable
  count caveat rather than folded into the denominators, because the abstract available in the
  reference cache does not mention her.

  What is not here. No animal model of MRPS7 deficiency was found. No dataset accession is
  recorded, because no MRPS7 patient omics deposit was identified. No prevalence rate, no
  natural-history series, no treatment evidence, and no residual-activity percentages exist for
  this entity; the numbers behind the "combined deficiency of complexes I, III and IV" statement
  are not in the abstract, which is all that was retrievable for the 2015 paper.

  The gene-symbol trap. MRPS7 carries a substantial oncology literature - prognostic gene
  signatures, and a mechanistic role in cisplatin resistance in nasopharyngeal carcinoma via
  beta-catenin stabilisation. A search on the symbol returns those in preponderance over the two
  patient reports.

📚

References & Deep Research

References

3

PMID:25556185

Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia.

No top-level findings curated for this source.

PMID:36421788

Integral Role of the Mitochondrial Ribosome in Supporting Ovarian Function: MRPS7 Variants in Syndromic Premature Ovarian Insufficiency.

No top-level findings curated for this source.

PMID:38855161

Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope and shape. entry_type DISEASE, standalone, consistent with how dismech curates the rest of the numbered COXPD series (defects 4, 7, 13, 21, 23, 26, 30 and deficiencies 42, 48, 51 are all separate files). The stub is deleted because MONDO:0054741 is now bound by this entry's disease_term. Relationship with Perrault_Syndrome. This is the one thing a reviewer should look at hardest. MRPS7 is already curated as a causative gene in `Perrault_Syndrome`, on the strength of the same two publications, and that entry's own notes describe exactly this pattern - a pleiotropic gene whose other phenotype is curated separately and cross-referenced rather than imported. This entry follows the same convention in the opposite direction: it models the hepatorenal, lactic-acidemic presentation that OMIM 617872 names, records the ovarian phenotype because two of the three published patients have it, and points at `Perrault_Syndrome` rather than re-curating the Perrault phenotype. An OPEN_QUESTION discussion records that the two may be one disease seen at two ages, which three patients cannot settle. Gene identity. Neither MONDO nor the stub records a causal gene for MONDO:0054741. MRPS7 (hgnc:14499) was resolved through the OMIM exact match - MONDO:0054741 to OMIM:617872 to NCBI Gene 51081 in mim2gene_medgen - and is corroborated by the founding paper's own title. Note hgnc:14499 and not hgnc:14508, which is MRPS22, a different mitoribosomal small-subunit gene curated elsewhere in this repository. ClinGen and OMIM are not cited as evidence items, and that is deliberate. ClinGen's June 2024 MRPS7 assertion (Limited) is absent from the ClinGen gene-validity snapshot pinned in `data/clingen/MANIFEST.yaml`, and building a cache file from a newer, unpinned download would commit an artifact that cannot be reproduced from the pin - a manifest repin is its own change, not part of a curation PR. Both the ClinGen classification and the OMIM provisional flag are recorded in the `genetic` notes with their sources named, and both were read directly from the respective downloads rather than inferred. Module conformance and node naming. The Impaired Oxidative Phosphorylation node declares `conforms_to: mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress`, following the sibling entry COXPD48, which conforms its equivalent node to the same target. Only the oxidative-phosphorylation half of that module node's effector state is claimed: the module also pairs it with rising reactive oxygen species, and no ROS measurement has been reported in an MRPS7 patient. One node name still reads as a bundle and is kept deliberately: "Reduced 12S rRNA and Impaired Small Subunit Assembly". The two are one claim rather than two - 12S rRNA transcript level is the measurement that was made, and small-subunit assembly is what it stands for - and the node and the model link both say so, including that no gradient or complexome profile of the mitoribosome in patient cells exists. Naming it for the assembly alone would assert a measurement that was not made; naming it for the rRNA alone would lose the mechanism. Two corrections this entry took from its deep-research report. The report is on the right disease - MRPS7 is mentioned 45 times and dominates its gene counts - and it independently resolved the same gene and OMIM numbers this entry did. It corrected the standardised mitoribosome name for the protein, which is uS7m rather than mS7, and it reports from the 2022 paper's full text an additional similarly affected sister whose genotype was not given. The first correction is applied; the second is recorded in the prevalence notes as an unverifiable count caveat rather than folded into the denominators, because the abstract available in the reference cache does not mention her. What is not here. No animal model of MRPS7 deficiency was found. No dataset accession is recorded, because no MRPS7 patient omics deposit was identified. No prevalence rate, no natural-history series, no treatment evidence, and no residual-activity percentages exist for this entity; the numbers behind the "combined deficiency of complexes I, III and IV" statement are not in the abstract, which is all that was retrievable for the 2015 paper. The gene-symbol trap. MRPS7 carries a substantial oncology literature - prognostic gene signatures, and a mechanistic role in cisplatin resistance in nasopharyngeal carcinoma via beta-catenin stabilisation. A search on the symbol returns those in preponderance over the two patient reports.

Review round 1: narrow three GO bindings, add module conformance, rename a node (COXPD34) · 2026-09-09T18:59:24Z · View source

Response to the ai4c-reviewer round on PR #11547. Item 1, no deep-research artifact: already addressed. The falcon run returned after the PR was opened and landed in commit b82d3e2cb3, before this round. It passed the manual preflight fallback (preflight-dr returns SKIP because MONDO records no causal gene for MONDO:0054741 - which is the gap this entry fills - and MRPS7 is mentioned 45 times, dominating the report's gene counts). That commit also took a correction from it: MRPS7 is uS7m in the standardised mitoribosome nomenclature, not mS7. Item 2, GO:0000028 over-general: accepted. The node's preferred_term already said 'mitochondrial small ribosomal subunit assembly' and GO has exactly that term. Rebound to GO:0180026. The old binding was the cytosolic-inclusive parent and did claim something broader than the mechanism. Suggestion 4, GO:0019843: accepted. MRPS7 binds 12S rRNA, which is a small-subunit rRNA, so GO:0070181 'small ribosomal subunit rRNA binding' is exactly right and the generic rRNA-binding parent was loose. This added one row to cache/go/terms.csv and one to the molecular-function enum cache. Suggestion 5, GO:0140053 on the combined-deficiency node: accepted, and the reviewer's reading is correct - 'mitochondrial gene expression, DECREASED' annotated the upstream cause, which the pathograph already models as its own node two steps earlier. Replaced with GO:0022900 'electron transport chain', DECREASED, which is what a deficiency of complexes I, III and IV actually is. Suggestion 3, module conformance: accepted. The Impaired Oxidative Phosphorylation node now declares conforms_to mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress, following COXPD48, which conforms its equivalent node to the same target with the same GO:0006119 annotation. GO:0006119 was added alongside the existing GO:0042775. Only the oxidative-phosphorylation half of the module node's effector state is claimed: the module pairs it with rising reactive oxygen species, and no ROS measurement exists in an MRPS7 patient, so asserting it would import a claim from the module rather than from this disease. That is stated in the node description and in the entry notes. Suggestion 6, node names that bundle: partly accepted. 'Impaired Oxidative Phosphorylation and Cytosolic Redox Shift' was renamed to 'Impaired Oxidative Phosphorylation' - the redox shift is already its own downstream node, so the old name was redundant with the node it points at. Its one incoming downstream target was updated in the same edit and check-entity-refs and check-causal-targets re-run clean. 'Reduced 12S rRNA and Impaired Small Subunit Assembly' is kept, and the entry notes now say why: the two are one claim, since 12S rRNA transcript level is the measurement that was made and small-subunit assembly is what it stands for. Naming it for the assembly alone would assert a measurement nobody made; naming it for the rRNA alone would lose the mechanism. Validation after the edits: just validate passed with 42/42 snippets verified; check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms and check-folded-hyphens all clean. One new term-cache row and one new enum-cache row, both for GO:0070181.

Correct uS7m nomenclature and record DR count caveat (COXPD34) · 2026-09-09T18:32:34Z · View source

Follow-up to the creation record in the same session, after the falcon deep-research run for this disorder returned. Preflight outcome. preflight-dr returns SKIP, because MONDO records no causal gene for MONDO:0054741 and the gene-identity check therefore cannot discriminate - which is exactly the case this entry exists to resolve. The manual fallback was done instead: MRPS7 is mentioned 45 times and dominates the report's gene counts, so the report is on the right disease and not a substituted entity. The OMIM warning is benign: the extractor picked up 611974, which is the MRPS7 *gene* MIM (NCBI Gene 51081), while the report's own text correctly states OMIM phenotype 617872 alongside it. The report independently resolved the same gene and the same OMIM numbers this entry had resolved from mim2gene_medgen. Two things taken from the report. First, a correction that is applied. The entry described MRPS7 as 'also written mS7 in the standardised mitoribosome nomenclature'. That is wrong: MRPS7 is homologous to bacterial S7 and is designated uS7m, the 'u' prefix marking a subunit conserved from the bacterial ribosome rather than a mitochondria-specific addition. The pathophysiology node name was renamed from 'Destabilization of the mS7 Protein of the Mitoribosomal Small Subunit' to '... uS7m ...', and the one downstream target pointing at it was updated in the same edit; check-entity-refs and check-causal-targets were re-run and are clean. Second, a claim that is recorded but not acted on. The report states, from the full text of the 2022 paper, that the second family also included a similarly affected sister whose genotype was not reported. The abstract is all that was retrievable into the reference cache and does not mention her, so this could not be verified against a quotable source. It is recorded as a caveat in the prevalence notes rather than folded into the denominators, with the observation that if she is real every 'of 3' figure becomes an 'of 4' with an ungenotyped member and no frequency band changes. Nothing else in the entry was changed on the strength of the report; the report's clinical and mechanistic account agrees with what was already curated from the primary references. Validation after the edit: just validate passed with 42/42 snippets verified, check-folded-hyphens, check-duplicate-keys, check-entity-refs and check-causal-targets all clean.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 29 citations 2026-09-09T11:25:52.972243

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Combined Oxidative Phosphorylation Deficiency 34
MONDO ID: MONDO:0054741 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Combined Oxidative Phosphorylation Deficiency 34 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Combined Oxidative Phosphorylation Deficiency 34: research report

Executive summary

Combined oxidative phosphorylation deficiency 34 (COXPD34) is an ultra-rare, autosomal-recessive nuclear mitochondrial translation disorder caused by biallelic MRPS7 variants. MRPS7/uS7m is a component of the mitochondrial 28S small ribosomal subunit that binds mitochondrial 12S rRNA. Defective MRPS7 destabilizes the small subunit, impairs translation of mtDNA-encoded oxidative-phosphorylation proteins, and produces combined respiratory-chain deficiency. The best-established manifestations are congenital or childhood sensorineural hearing loss, lactic acidemia, hypoglycemia, progressive hepatic and renal dysfunction, and—in females surviving to reproductive age—premature ovarian insufficiency (POI)/Perrault-spectrum disease. Evidence remains exceptionally limited: four clinically affected females from two unrelated families have been described, only three of whom were molecularly documented in the cited reports. Consequently, prevalence, penetrance, robust phenotype frequencies, survival rates, and genotype–phenotype relationships are unknown. (kline2022integralroleof pages 2-4, menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 1-2)

The foundational primary report was published online 2 January 2015: Menezes et al., Human Molecular Genetics 24:2297–2307, PMID 25556185, DOI/URL: https://doi.org/10.1093/hmg/ddu747. Its abstract states: “Pulse labeling of mitochondrial protein synthesis products revealed impaired mitochondrial protein synthesis in patient fibroblasts,” and wild-type MRPS7 rescued respiratory-chain activity and 12S-rRNA abundance. (menezes2015mutationinmitochondrial pages 1-2)

An independent report published 14 November 2022 expanded the phenotype to syndromic POI/Perrault syndrome: Kline et al., Genes 13:2113, DOI/URL: https://doi.org/10.3390/genes13112113. Its abstract states: “This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome.” (kline2022integralroleof pages 1-2)

Evidence unit / publication	Genotype	Patient count	Core phenotype and onset	Key biochemical / pathology evidence	Outcome / treatment	Evidence type and limitations
Menezes et al., Human Molecular Genetics (published January 2, 2015); PMID: 25556185; DOI: 10.1093/hmg/ddu747	Homozygous MRPS7 c.550A>G, p.(Met184Val), rs115047866; affected sisters homozygous, parents and unaffected sister heterozygous	2 affected sisters	Both had profound congenital bilateral sensorineural deafness and childhood lactic acidemia. P1 developed recurrent emesis and failure to thrive in infancy, hypoglycemia <0.5 mmol/L and lactate 4.1 mmol/L at 13 months, then progressive hepatic and renal failure. P2 had intermittent childhood hyperlactatemia/hypoglycemia, mild learning difficulties, failed puberty, primary hypogonadism at 16 years, mildly elevated TSH (6.75 mIU/L), and primary adrenal failure.	Liver respiratory-chain activities were deficient in complexes I, III, and IV: P1/P2 complex I 7/6 (reference 10–21), complex III 7.4/4.5 (9–14), and complex IV 0.2/1.1 (1.1–1.6) nmol/min/mg or /min/mg as reported. P1 muscle complex III was 11.6 (14–67); other muscle activities were largely preserved. P2 renal biopsy at 13 years showed tubular atrophy/dilatation and giant mitochondria up to 5.5 μm versus normal 0.5–1.0 μm, with increased matrix and reduced cristae. P1 fibroblasts showed near-absent MRPS7, reduced 12S rRNA, impaired mitochondrial translation, reduced OXPHOS proteins, complexes I/IV dysfunction, mitochondrial-network fragmentation, and significantly reduced ATP production (P<0.003). Wild-type—but not mutant—MRPS7 restored 12S rRNA and respiratory-chain activity.	P1 received resuscitation, antibiotics, nutritional support, ventilation, and hemofiltration; a left parieto-occipital infarct precluded transplantation, and she died at 14 years 5 months after intensive support was withdrawn. P2 received cochlear implantation, estrogen replacement, and low-dose hydrocortisone; later follow-up reported combined liver–renal transplantation at 25 years with a positive outcome.	Human familial case series plus patient-fibroblast rescue experiments; strongest direct causal evidence. Only one family, no controlled treatment data, ancestry not specified, and marked intrafamilial variability limit frequency and prognostic inference. Historical allele estimates were heterozygosity 0.002 in dbSNP and 0.67% in an in-house CAG dataset, not current gnomAD frequencies. (menezes2015mutationinmitochondrial pages 1-2, menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 3-4, menezes2015mutationinmitochondrial pages 6-7)
Kline et al., Genes (published November 14, 2022); DOI: 10.3390/genes13112113 — proband	Compound heterozygous MRPS7 c.373A>T, p.(Lys125*) and c.536G>A, p.(Arg179His), demonstrated in trans; both classified likely pathogenic by the authors	1 molecularly characterized proband	Sensorineural hearing loss diagnosed at 9 years; normal puberty followed by secondary amenorrhea and premature ovarian insufficiency diagnosed at 25 years; Hashimoto disease. FSH 102 IU/L, LH 34 IU/L, estradiol 29 pg/mL, AMH 0.15 ng/mL, TSH 12.89 mIU/L, and anti-TPO 102 IU/mL.	Ultrasound at 25 years showed small ovaries: right 18×4.5 mm with two microfollicles and left 14×6 mm without visible follicles. Karyotype/microarray showed 46,XX; FMR1-premutation and ovarian-autoantibody testing were negative. p.(Lys125*) was predicted to undergo nonsense-mediated decay; structural modeling predicted p.(Arg179His) would disrupt interactions with Glu153 and Asp176. No patient-cell functional assay was reported.	Hashimoto disease was described as well managed. Bone mineral density was not osteoporotic. No disease-modifying therapy or treatment-response data were reported; the authors highlighted potential benefits of early hormone replacement or oocyte collection for mitochondrial-disease-associated POI generally.	Human single-case report with WES, Sanger validation, phasing, clinical endocrine testing, and computational modeling. Independent allelic replication supports causality, but lack of functional validation, parental DNA, longitudinal outcome, and disease-specific treatment evidence limits interpretation. (kline2022integralroleof pages 4-5, kline2022integralroleof pages 5-8, kline2022integralroleof pages 1-2, kline2022integralroleof pages 8-9)
Kline et al. (2022) — clinically affected sister of the new proband	Presumed familial MRPS7-related disease; sister’s genotype was not reported	1 clinically affected sister	Congenital hearing loss and POI diagnosed at 21 years	No biochemical, imaging, histopathologic, or functional data reported	Treatment and outcome not reported	Human phenotype-only familial evidence; cannot independently confirm genotype, mechanism, or biochemical COXPD34. (kline2022integralroleof pages 4-5, kline2022integralroleof pages 5-8)
Combined published human evidence through 2022	Three reported disease-associated alleles: c.550A>G p.(Met184Val), c.373A>T p.(Lys125*), and c.536G>A p.(Arg179His)	4 clinically affected females across 2 unrelated families; 3 molecularly documented in the cited reports	Sensorineural hearing loss occurred in all 4 reported individuals; ovarian insufficiency/hypogonadism was documented in the 3 who survived to an assessable reproductive age. Severe progressive hepatorenal disease was documented in the original sisters; biochemical combined OXPHOS deficiency was demonstrated only in that family.	Direct functional evidence is confined to p.(Met184Val) patient fibroblasts. The nearby p.(Arg179His) and p.(Met184Val) residues lie within the predicted ribosomal-protein S7 domain (codons 82–234), which interacts with 12S rRNA.	No curative or genotype-specific therapy and no controlled treatment response have been reported. Organ transplantation and endocrine, adrenal, auditory, nutritional, renal, and intensive supportive interventions were used in individual patients.	Ultra-small, ascertainment-biased literature; percentages are descriptive rather than population estimates. Penetrance, prevalence, incidence, carrier frequency, sex ratio, survival rates, and robust genotype–phenotype correlations remain unknown. (kline2022integralroleof pages 2-4, kline2022integralroleof pages 9-10)

Table: Disease-specific clinical, genetic, biochemical, and functional evidence for MRPS7-related combined oxidative phosphorylation deficiency 34. The table highlights the very small evidence base, exact reported measurements, outcomes, and major limitations.

1. Disease information

Definition and identifiers

COXPD34 is a Mendelian mitochondrial disorder in which defective mitochondrial protein synthesis causes deficiency of multiple OXPHOS complexes rather than an isolated respiratory-complex defect.

MONDO: MONDO:0054741.
OMIM phenotype: 617872, Combined oxidative phosphorylation deficiency 34.
Causal gene: MRPS7, mitochondrial ribosomal protein S7; OMIM gene 611974; Ensembl target ENSG00000125445.
Common names/synonyms: combined oxidative phosphorylation deficiency 34; COXPD34; MRPS7-related mitochondrial disease; MRPS7 deficiency. Phenotypic labels include MRPS7-related syndromic POI, MRPS7-related Perrault syndrome, and congenital sensorineural deafness with progressive hepatic/renal failure and lactic acidemia.
Orphanet, MeSH, ICD-10/ICD-11: no disease-specific identifiers were established in the retrieved evidence. In clinical coding, broader mitochondrial-metabolism, hearing-loss, renal, hepatic, and ovarian-insufficiency codes may be needed; these are not equivalent to a dedicated COXPD34 code.

Open Targets associates MONDO:0054741 with MRPS7 and cites PMID 25556185. This is consistent with the primary literature and corrects a potential nomenclature pitfall: COXPD34 is MRPS7-related, not GATB-related. (OpenTargets Search: Combined oxidative phosphorylation deficiency 34, webb2020mitochondrialtranslationdefects pages 12-13)

Evidence provenance

The disease definition is aggregated at the disease-resource level, but virtually all phenotype and natural-history knowledge comes from individual patients in two published families rather than registries, EHR-scale cohorts, or epidemiologic studies. The original family contributed two affected sisters; the second report described one molecularly characterized woman and one similarly affected sister whose genotype was not reported. (kline2022integralroleof pages 2-4, kline2022integralroleof pages 5-8)

2. Etiology

Causal factor

The primary cause is germline biallelic MRPS7 dysfunction, inherited autosomal recessively. MRPS7 encodes uS7m, a nuclear-encoded structural protein of the mitochondrial small ribosomal subunit. No infectious, toxic, lifestyle, or environmental primary cause is established. (webb2020mitochondrialtranslationdefects pages 12-13, menezes2015mutationinmitochondrial pages 1-2)

Genetic risk factors

Three disease-associated alleles are reported:

c.550A>G, p.(Met184Val), rs115047866, homozygous in the original affected sisters and heterozygous in both parents and an unaffected sister. The 2015 paper classified it as pathogenic after segregation, biochemical studies, protein modeling, and wild-type rescue. Historical databases reported dbSNP heterozygosity 0.002 and an in-house CAG frequency of 0.67%; these are not substitutes for a current ancestry-stratified gnomAD frequency. (menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 3-4)
c.373A>T, p.(Lys125*), a nonsense allele classified likely pathogenic in the 2022 report. It lies in exon 4 of 5 and was predicted to trigger nonsense-mediated decay, producing loss of function. (kline2022integralroleof pages 5-8, kline2022integralroleof pages 8-9)
c.536G>A, p.(Arg179His), a missense allele classified likely pathogenic in the 2022 report. Modeling predicted loss of salt-bridge/hydrogen-bond interactions involving Glu153 and Asp176. The two variants were experimentally phased in trans. (kline2022integralroleof pages 8-9)

The 2022 filtering pipeline considered alleles with MAF below 0.005 in 1000 Genomes and gnomAD, but exact current population frequencies for its two variants were not given in the retrieved text. Both p.Arg179His and p.Met184Val lie within the predicted S7 domain (codons 82–234). (kline2022integralroleof pages 4-5, kline2022integralroleof pages 9-10)

Environmental risk, protective factors, and gene–environment interaction

No validated environmental risk or protective factor is known. In the severe original patient, acute febrile illness/presumed bacterial peritonitis preceded terminal hepatorenal decompensation. The authors considered—but did not demonstrate—that antibiotics could have interfered with mitochondrial translation; they instead emphasized unsupervised disease progression and unknown genetic/environmental modifiers. This is hypothesis-level evidence, not an established gene–environment interaction. Gentamicin exposure deserves caution because aminoglycosides can be ototoxic and inhibit bacterial-like mitochondrial translation, but no MRPS7-specific sensitivity has been demonstrated. (menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 6-7)

No protective MRPS7 alleles, modifier genes, diet, supplements, exercise program, or avoidance strategy has been shown to alter penetrance or progression.

3. Phenotypes

Because only four clinically affected females are known, frequencies below are descriptive fractions of published cases, not population estimates.

Sensorineural hearing loss: 4/4 reported individuals; congenital and profound in the original sisters and the second proband’s sister, diagnosed at age 9 in the second proband. Severity ranged from childhood-onset to profound congenital bilateral deafness. Suggested HPO: Sensorineural hearing impairment (HP:0000407); Congenital sensorineural hearing impairment (HP:0008527); bilateral/profound qualifiers where appropriate. Cochlear implantation produced satisfactory speech acquisition in the original family. (kline2022integralroleof pages 5-8, menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 3-4)
Lactic acidemia/hyperlactatemia: reported in both original sisters; one documented level was 4.1 mmol/L at 13 months. It was intermittent and later mostly normal in the milder sister. Suggested HPO: Lactic acidosis (HP:0003128); Increased circulating lactate concentration (HP:0002151). (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 3-4)
Hypoglycemia: documented in both original sisters during childhood; one severe episode was below 0.5 mmol/L. It later resolved spontaneously in the milder sister. Suggested HPO: Hypoglycemia (HP:0001943); episodic qualifier. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 3-4)
Hepatic disease: both original sisters had liver pathology/biochemical deficiency and progressive hepatic dysfunction; one developed terminal liver failure and the other later underwent liver transplantation. Histology included hepatocyte swelling, mild steatosis, mild portal/Disse-space expansion, and grade 1–2 iron accumulation. Suggested HPO: Hepatic failure (HP:0001399), Hepatomegaly (HP:0002240), Hepatic steatosis (HP:0001397), abnormal liver morphology. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 2-3)
Renal disease: progressive renal dysfunction affected both original sisters. Biopsy showed tubular atrophy/dilatation, protein casts, and giant mitochondria up to 5.5 μm. Suggested HPO: Renal insufficiency (HP:0000083), Renal tubular atrophy (HP:0000092), abnormal renal-tubule morphology. (menezes2015mutationinmitochondrial pages 2-3)
POI/hypogonadism: present in all three females who survived long enough for reproductive assessment. Presentations included failed puberty/primary hypogonadism and primary amenorrhea, or normal puberty followed by secondary amenorrhea and POI at ages 21–25. Suggested HPO: Primary ovarian insufficiency (HP:0008209), Primary amenorrhea (HP:0000786), Secondary amenorrhea (HP:0000869), Delayed puberty (HP:0000823), Hypergonadotropic hypogonadism (HP:0000830). (kline2022integralroleof pages 5-8, kline2022integralroleof pages 9-10)
Endocrine abnormalities: primary adrenal failure was diagnosed in one original sister by short Synacthen testing; mild TSH elevation occurred in that patient. The 2022 proband had Hashimoto disease, TSH 12.89 mIU/L, and anti-TPO 102 IU/mL. Whether autoimmune thyroid disease is integral to MRPS7 deficiency is unresolved. Suggested HPO: Primary adrenal insufficiency (HP:0008207), Hypothyroidism (HP:0000821), Elevated serum TSH (HP:0002925). (kline2022integralroleof pages 5-8, menezes2015mutationinmitochondrial pages 3-4)
Growth/neurodevelopment: recurrent emesis and failure to thrive occurred in the severe original patient. Her motor/cognitive development remained normal at 4.5 years. The milder sister had mild learning difficulties; encephalopathy occurred secondary to organ failure rather than as a proven primary neurodegenerative phenotype. Suggested HPO: Failure to thrive (HP:0001508), Recurrent vomiting (HP:0002013), Mild intellectual disability/learning disability as clinically appropriate, Encephalopathy (HP:0001298) with secondary-cause annotation. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 3-4)
Laboratory/pathologic OXPHOS phenotype: combined complexes I, III, and IV deficiency in liver and reduced complexes I/IV in fibroblasts; ATP production was significantly reduced (P<0.003). Suggested HPO: Abnormality of mitochondrial metabolism (HP:0012103) and Combined oxidative phosphorylation defect where locally available. (menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 6-7)

Functional and quality-of-life burden

Profound hearing loss affects communication and education; cochlear implantation improved speech acquisition. Ovarian insufficiency causes infertility and requires endocrine/fertility counseling. Hepatorenal failure led to dialysis-level support, transplantation, encephalopathy, prolonged intensive care, and death in one patient. No EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life instrument has been reported. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 3-4)

4. Genetic and molecular information

Gene: MRPS7; OMIM 611974; protein uS7m/MRPS7; UniProt Q9Y2R9. It is a nuclear gene; variants are constitutional/germline, not somatic. (menezes2015mutationinmitochondrial pages 7-8)
Variant classes: one nonsense predicted loss-of-function allele and two missense alleles predicted or demonstrated to destabilize protein/small-subunit function.
Functional consequence: predominantly loss of function. p.Met184Val caused near-total absence of MRPS7 protein in fibroblasts, reduced 12S rRNA, defective mitochondrial translation, and reduced respiratory-chain activity. Wild-type—but not mutant—complementation rescued molecular and biochemical abnormalities, arguing against gain of function or dominant-negative action. (menezes2015mutationinmitochondrial pages 3-4, menezes2015mutationinmitochondrial pages 6-7)
Chromosomal abnormalities: none causal. The original affected sisters shared an approximately 1-Mb run of homozygosity at 17q25.1, possibly reflecting remote shared ancestry, although the parents reported no consanguinity. The 2022 proband had a normal 46,XX complement by karyotype/microarray. (menezes2015mutationinmitochondrial pages 3-4, kline2022integralroleof pages 4-5)
Modifier genes: none identified. Intrafamilial severity variability implies possible modifiers but provides no specific locus.
Epigenetics: no disease-specific DNA-methylation, chromatin, or histone-modification signature is reported.

ClinVar submissions for the 2022 alleles were reported as SCV002574697–SCV002574698. (kline2022integralroleof pages 10-12)

5. Environmental information

No toxin, radiation, pollution, occupation, smoking, alcohol, diet, exercise pattern, or infectious agent causes COXPD34. Intercurrent infection/metabolic stress may plausibly precipitate decompensation, as in other mitochondrial disorders, but only a single acute terminal episode is documented here. No zoonotic or transmissible component exists. The appropriate knowledge-base representation is therefore “not established/not applicable,” rather than absence being interpreted as proof of no effect. (menezes2015mutationinmitochondrial pages 2-3, kline2022integralroleof pages 2-4)

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic germline MRPS7 pathogenic variants lead to reduced abundance or structural instability of uS7m; near-total protein loss was demonstrated for p.Met184Val, while p.Lys125* loss and p.Arg179His destabilization are predicted. (kline2022integralroleof pages 8-9, menezes2015mutationinmitochondrial pages 6-7)
Defective uS7m leads to unstable assembly of the mitochondrial 28S small subunit and defective binding/incorporation of 12S rRNA. MRPS7’s S7 domain interacts with the 3′ head of 12S rRNA; reduced 12S but preserved 16S rRNA was demonstrated in patient fibroblasts. (kline2022integralroleof pages 9-10, menezes2015mutationinmitochondrial pages 3-4)
Small-subunit instability leads to 12S-rRNA degradation and impaired mitochondrial translation. Pulse-labeling and reduced MT-CO1/MT-CO2 demonstrated reduced synthesis/abundance of mtDNA-encoded products. (menezes2015mutationinmitochondrial pages 1-2, menezes2015mutationinmitochondrial pages 6-7)
Deficient synthesis of mtDNA-encoded subunits leads to defective assembly/activity of multiple OXPHOS complexes, principally I, III, and IV. Complex II is nuclear encoded and comparatively preserved. (menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 6-7)
Combined OXPHOS dysfunction leads to reduced ATP generation, compensatory mitochondrial proliferation/network fragmentation, and lactate accumulation. Reduced ATP production and fragmented fibroblast mitochondrial networks were demonstrated; tissue-energy failure is the downstream interpretation. (menezes2015mutationinmitochondrial pages 3-4, menezes2015mutationinmitochondrial pages 6-7)
Energy failure in high-demand tissues leads to cochlear dysfunction, hepatocellular injury, renal tubular mitochondrial enlargement/dysfunction, episodic hypoglycemia, and systemic lactic acidemia. The organ-specific link is strongly supported clinically and biochemically, although exact tissue-selectivity mechanisms remain unresolved. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 2-3)
Branch A—ovary: mitochondrial translation/OXPHOS insufficiency is inferred to reduce oocyte/granulosa-cell energy support and increase oxidative stress, leading to follicular atresia, depletion of viable oocytes, and POI. This branch is biologically plausible and supported by the reproductive phenotype, but it was not directly tested in MRPS7 patient ovarian tissue. (kline2022integralroleof pages 9-10)
Branch B—advanced organ failure: progressive hepatic and renal dysfunction leads to metabolic encephalopathy and critical illness; in one patient a cerebral infarct during decompensation precluded transplantation and preceded death. (menezes2015mutationinmitochondrial pages 2-3)

Pathways and processes

The primary pathway is mitochondrial gene expression/translation feeding OXPHOS, not canonical Wnt, MAPK, PI3K–AKT, or mTOR signaling. Relevant GO suggestions include mitochondrial translation (GO:0032543), mitochondrial ribosome assembly (GO:0061668), mitochondrial respiratory-chain complex assembly (GO:0033108), oxidative phosphorylation (GO:0006119), ATP metabolic process (GO:0046034), and cellular response to oxidative stress (GO:0034599). The 2024 review emphasizes that mtDNA encodes 13 OXPHOS subunits and that mitochondrial-translation disorders are frequently multisystemic because high-energy-demand tissues are vulnerable. (antolinezfernandez2024molecularpathwaysin pages 1-2)

Relevant cellular compartments are mitochondrial matrix (GO:0005759), mitochondrial small ribosomal subunit (GO:0005763), mitochondrial ribosome (GO:0005761), mitochondrial inner membrane (GO:0005743), and respiratory-chain complexes I/III/IV.

Suggested cell ontology targets include renal tubular epithelial cell, hepatocyte (CL:0000182), cochlear hair cell, oocyte (CL:0000023), ovarian granulosa cell (CL:0000501), and fibroblast for the experimental model. Exact CL identifiers should be validated against the current ontology release before database ingestion.

Molecular profiling and advanced technologies

Disease-specific profiling is limited to targeted immunoblotting, qPCR, radiolabeled translation assays, enzymology, ATP measurement, and mitochondrial imaging in fibroblasts. There is no COXPD34-specific bulk transcriptome, unbiased proteome, metabolome, lipidome, single-cell, spatial-transcriptomic, or multi-omic dataset. Recent 2024 work in broader mitochondrial cohorts showed that fibroblast mass-spectrometry proteomics can classify biochemical/genetic groups and aid VUS interpretation, but this is an emerging diagnostic application, not validated specifically for MRPS7. Likewise, a 2024 French cohort found 397 molecularly confirmed cases across 172 genes and supported WES/WGS over panels for possible mitochondrial disease; MRPS7-specific performance was not provided. (rouzier2024primarymitochondrialdisorders pages 1-2, rouzier2024primarymitochondrialdisorders pages 8-11)

7. Anatomical structures affected

Primary organs: inner ear/cochlea; liver; kidney, particularly renal tubules; ovary.
Secondary/variable systems: adrenal and thyroid endocrine axes; central nervous system during metabolic/organ failure; gastrointestinal/nutritional system through recurrent emesis and failure to thrive.
Tissues/cells: cochlear sensory epithelium/hair cells, hepatocytes, renal tubular epithelial cells, ovarian follicles/oocytes/granulosa cells. Direct disease histology exists for liver, muscle, and kidney; ovarian and cochlear cellular mechanisms are inferred.
Subcellular: mitochondrial matrix, 28S small mitoribosomal subunit, 12S rRNA, inner-membrane OXPHOS machinery.

Suggested UBERON terms include cochlea (UBERON:0001844), liver (UBERON:0002107), kidney (UBERON:0002113), renal tubule (UBERON:0001231), ovary (UBERON:0000992), adrenal gland (UBERON:0002369), and brain (UBERON:0000955). Hearing loss was bilateral; no consistent lateralized organ disease is known. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 2-3)

8. Temporal development

COXPD34 spans a congenital-to-adult continuum:

Congenital/infantile phase: congenital deafness; infancy-onset vomiting, failure to thrive, hypoglycemia, and lactic acidemia in severe disease.
Childhood phase: hearing impairment, intermittent metabolic abnormalities, mild learning difficulty in one patient, and emerging liver/renal dysfunction.
Adolescent phase: potentially rapid decompensation with hepatorenal failure; one death occurred at 14 years 5 months. Failed puberty/primary hypogonadism was diagnosed at 16 in another patient.
Young-adult phase: progressive organ dysfunction may culminate in combined liver–kidney transplantation; milder patients may present with POI at ages 21–25 after congenital/childhood hearing loss. (kline2022integralroleof pages 5-8, kline2022integralroleof pages 9-10, menezes2015mutationinmitochondrial pages 2-3, menezes2015mutationinmitochondrial pages 3-4)

The course is chronic and variably progressive, with episodic metabolic crises. Spontaneous biochemical improvement is possible—childhood hypoglycemia resolved and lactate often normalized in one patient—but this is not remission of the underlying genetic disorder. Critical periods include infancy during metabolic stress, adolescence during organ decline, and pre-/peripuberty for endocrine surveillance and fertility preservation. No validated staging system exists.

9. Inheritance and population

Inheritance is autosomal recessive. In the original family, both affected sisters were homozygous and both parents plus an unaffected sister were heterozygous. The second proband’s two variants were confirmed in trans, although parental DNA was unavailable. (menezes2015mutationinmitochondrial pages 2-3, kline2022integralroleof pages 8-9)

For two carrier parents, standard Mendelian counseling gives a 25% affected, 50% carrier, and 25% unaffected/non-carrier probability per pregnancy, assuming both parental variants and phase are confirmed. Penetrance among biallelic individuals cannot be estimated. Expressivity is clearly variable—even within one family—but anticipation, germline mosaicism, and founder effects are unreported. A shared 17q25.1 homozygous segment raises possible remote common ancestry for the original parents; there was no acknowledged consanguinity. (menezes2015mutationinmitochondrial pages 3-4)

Disease-specific prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, and geographic distribution are unknown. All reported affected individuals were female, but this reflects an extremely small sample and ascertainment through POI; it cannot establish female predominance. For context only, a 2024 French study cites primary mitochondrial disease prevalence of at least 20 per 100,000 and estimated lifetime risk of 48.4 per 100,000 for 249 recessive mitochondrial disorders combined; these figures must not be assigned to COXPD34. (rouzier2024primarymitochondrialdisorders pages 1-2)

10. Diagnostics

Recommended approach

Clinical suspicion: bilateral sensorineural hearing loss plus unexplained lactic acidemia, hypoglycemia, liver/renal dysfunction, or female POI/failed puberty should prompt consideration of MRPS7 disease.
Baseline laboratory assessment: plasma lactate, glucose, blood gas, liver enzymes/synthetic function, renal function/electrolytes, urinalysis; consider plasma amino acids, acylcarnitines, urine organic acids, and endocrine testing. These tests support mitochondrial disease but are not specific.
System surveillance: audiology; abdominal ultrasound; renal and hepatic assessment; ECG/echocardiography despite no established cardiomyopathy in reported MRPS7 patients; neurologic examination and brain MRI/EEG if encephalopathy or seizures occur.
Reproductive/endocrine assessment: pubertal progression, menstrual history, FSH, LH, estradiol, AMH, TSH/free T4, thyroid antibodies where indicated, and adrenal testing when clinically suspected. The 2022 proband met POI criteria with menstrual disturbance and FSH above 20 mIU/mL on two occasions. (kline2022integralroleof pages 4-5)
First-line molecular testing: trio WES or WGS including nuclear mitochondrial genes and mtDNA analysis is preferred for a heterogeneous presentation. A comprehensive mitochondrial/hearing-loss/Perrault panel including MRPS7 is reasonable where exome/genome testing is unavailable. Recent cohort evidence favors WES/WGS over limited panels for “possible” mitochondrial disease. (rouzier2024primarymitochondrialdisorders pages 1-2, rouzier2024primarymitochondrialdisorders pages 8-11)
Variant confirmation: Sanger confirmation, parental segregation/phasing, population-frequency assessment, ACMG/AMP classification, and ClinVar review.
Functional confirmation for novel/VUS alleles: patient fibroblast MRPS7 immunoblot, 12S-versus-16S rRNA qPCR, mitochondrial translation pulse-labeling, OXPHOS protein/complex assessment, respiratory-chain enzymology, ATP or oxygen-consumption assays, and ideally wild-type complementation. The original study’s rescue experiments constitute the disease-specific reference assay. (menezes2015mutationinmitochondrial pages 1-2, menezes2015mutationinmitochondrial pages 6-7)

Biopsy/pathology

Muscle may be deceptively mild or normal: original muscle oxidative stains were unremarkable and most respiratory activities were preserved, whereas liver showed severe combined deficiency. Therefore, a normal muscle study does not exclude COXPD34. Liver or kidney biopsy should be clinically driven, not routine solely for diagnosis. Renal electron microscopy may reveal giant mitochondria and reduced cristae. (menezes2015mutationinmitochondrial pages 2-3)

Tests generally not indicated

CMA/karyotype can exclude chromosomal causes of POI but does not diagnose sequence-level MRPS7 disease. FISH and repeat-expansion testing have no disease-specific role. mtDNA testing helps exclude alternative mitochondrial etiologies but COXPD34 is nuclear encoded. The original study found no common mtDNA mutation, mt-tRNA^Leu(UUR) defect, or large mtDNA rearrangement. (menezes2015mutationinmitochondrial pages 2-3)

Differential diagnosis

Major differentials include Perrault-spectrum genes (CLPP, HARS2, LARS2, ERAL1, RMND1, PRORP, TWNK, TFAM, HSD17B4, PEX6, GGPS1), other mitoribosomal disorders (MRPS2, MRPS14, MRPS16, MRPS22, MRPS23, MRPS25, MRPS34, MRPS39, MRPL3/12/24/44), mtDNA-related deafness, Alström syndrome, mitochondrial depletion syndromes, POLG-spectrum disease, primary hepatic/renal metabolic disorders, autoimmune POI, FMR1 premutation, and gonadotoxic/acquired causes. The second proband had normal 46,XX testing, negative FMR1-premutation testing, and negative ovarian autoantibodies. (kline2022integralroleof pages 2-4, kline2022integralroleof pages 4-5)

Screening

COXPD34 is not an established population newborn-screening condition and lacks a validated dried-blood-spot biomarker or proven presymptomatic disease-modifying treatment. Appropriate screening is targeted: cascade testing of relatives, early audiology, metabolic/organ surveillance in biallelic children, and pubertal/ovarian monitoring in affected females.

11. Outcome and prognosis

No 5- or 10-year survival data, life-expectancy estimates, mortality rates, or validated prognostic biomarkers exist. Observed outcomes range from death at 14 years 5 months after progressive hepatorenal failure to survival into adulthood with successful combined liver–renal transplantation, and to relatively mild adult Perrault-spectrum disease without reported major hepatic/renal involvement. (kline2022integralroleof pages 5-8, kline2022integralroleof pages 9-10, menezes2015mutationinmitochondrial pages 2-3)

Potential adverse prognostic indicators—based only on the original family—include early persistent lactic acidemia/hypoglycemia, failure to thrive, progressive hepatic and renal biochemical abnormalities, and encephalopathy. Genotype alone is not currently predictive: homozygous p.Met184Val produced markedly different severity in sisters. Morbidity includes deafness, infertility/endocrine replacement needs, chronic organ failure, learning difficulties, hospitalization, dialysis/intensive support, and transplantation. Recovery of established multisystem disease is not documented, although organ replacement and symptom-directed treatments can substantially improve function.

12. Treatment

There is no approved MRPS7-targeted or disease-modifying treatment, no controlled trial, and no relevant COXPD34-specific NCT identified in the clinical-trial search.

Documented real-world interventions

Cochlear implantation improved speech acquisition and was tolerated in the original sisters. Suggested NCIt intervention concept: Cochlear Implantation. (menezes2015mutationinmitochondrial pages 2-2, menezes2015mutationinmitochondrial pages 3-4)
Estrogen/hormone replacement produced a good endocrine response in the patient with failed puberty/primary hypogonadism. Suggested NCIt: Hormone Replacement Therapy and Estrogen Therapy. (menezes2015mutationinmitochondrial pages 3-4)
Hydrocortisone replacement was used for primary adrenal failure. Suggested NCIt: Hydrocortisone Therapy.
Nutrition/metabolic-crisis support: avoidance of prolonged fasting, prompt glucose-containing fluids during catabolism, correction of hypoglycemia/acidosis, and specialist nutrition are rational general mitochondrial-care measures; only nasogastric renourishment and acute resuscitation are directly reported. (menezes2015mutationinmitochondrial pages 2-3)
Renal/hepatic support: hemofiltration was used during critical illness; one patient later had combined liver–renal transplantation with a positive reported outcome. Suggested NCIt: Hemofiltration, Kidney Transplantation, and Liver Transplantation. (kline2022integralroleof pages 9-10, menezes2015mutationinmitochondrial pages 2-3)
Rehabilitation: audiology, speech/language therapy, educational support, physical/occupational therapy as needed, and fertility/endocrine counseling.

No evidence supports a specific “mitochondrial cocktail,” coenzyme Q10, riboflavin, thiamine, antioxidants, ketogenic diet, immunotherapy, stem-cell treatment, gene therapy, RNA therapy, or CRISPR treatment in COXPD34. Pharmacogenomic dosing rules do not exist. The in-vitro rescue by wild-type MRPS7 provides proof of causal reversibility at the cellular level, not a currently deliverable human gene therapy. (menezes2015mutationinmitochondrial pages 1-2)

A practical management algorithm is: molecular confirmation → multidisciplinary mitochondrial/audiology/hepatology/nephrology/endocrinology assessment → crisis-prevention plan and longitudinal organ surveillance → early hearing rehabilitation → pubertal/ovarian surveillance and fertility preservation discussion → transplant evaluation for progressive organ failure.

13. Prevention

The mutation cannot currently be prevented by lifestyle modification.

Primary prevention: carrier testing for the reproductive partner of a known carrier; prenatal diagnosis or preimplantation genetic testing for a confirmed familial genotype; donor gametes or adoption according to patient preference and local regulation.
Secondary prevention: cascade testing of siblings/relatives; early audiology; serial liver, kidney, glucose/lactate, pubertal, ovarian, thyroid, and adrenal assessment. Earlier recognition may prevent delayed cochlear rehabilitation, adrenal crisis, or missed fertility-preservation opportunities.
Tertiary prevention: avoid prolonged fasting/dehydration, provide rapid treatment during infection or surgery, review potentially mitochondrial-toxic medications, manage hearing and endocrine deficiencies, and monitor organ decline before irreversible decompensation.

No vaccine prevents COXPD34; routine immunization is nevertheless important to reduce infectious stress. Genetic counseling should emphasize autosomal-recessive recurrence risk, uncertain prognosis, and substantial intrafamilial variability. Early oocyte/embryo preservation may be considered before ovarian reserve is lost, but no MRPS7-specific success data exist. (kline2022integralroleof pages 9-10)

14. Other species and natural disease

MRPS7 is evolutionarily conserved and mitoribosomal small-subunit biology is shared broadly across eukaryotes. However, no naturally occurring companion-animal, livestock, or wildlife syndrome directly homologous to human MRPS7-related COXPD34 was identified. Accordingly:

Natural veterinary disease/breed association: none established.
Zoonotic transmission: not applicable.
Cross-species transmission: not applicable.
Comparative relevance: conservation supports variant interpretation and model development, but does not by itself establish a natural animal disease.

Species and ortholog NCBI Gene/Taxon identifiers should be obtained directly from the current NCBI/Alliance release before database ingestion rather than inferred from the clinical papers.

15. Model organisms

Established disease model

The only direct COXPD34 model is primary patient fibroblasts carrying homozygous p.Met184Val. These recapitulated near-absent MRPS7, reduced 12S rRNA, defective mitochondrial translation, lower MT-CO1/MT-CO2 and OXPHOS proteins, complexes I/IV dysfunction, reduced ATP production, and mitochondrial-network fragmentation. Lentiviral wild-type complementation rescued 12S rRNA and respiratory-chain activity, making this a strong causal and assay-development model. Limitations are the use of one patient line, fibroblast rather than cochlear/hepatic/renal/ovarian cells, and incomplete recapitulation of tissue-specific disease. (menezes2015mutationinmitochondrial pages 3-4, menezes2015mutationinmitochondrial pages 6-7)

Unavailable models

No peer-reviewed MRPS7 COXPD34-specific knock-in/knockout mouse, rat, zebrafish, Drosophila, C. elegans, yeast disease model, patient iPSC, organoid, or CRISPR screen was identified. Generic mitoribosomal and ERAL1/CLPP models support the importance of small-subunit assembly and fertility but are not MRPS7 disease models. The 2024 review notes that mitochondrial-translation animal models frequently show tissue-specific and sometimes incomplete recapitulation, reinforcing the need for genotype-matched models. (antolinezfernandez2024molecularpathwaysin pages 1-2, antolinezfernandez2024molecularpathwaysin pages 14-15)

Priority future systems are: p.Met184Val and p.Arg179His knock-in mice or zebrafish; MRPS7-null/conditional tissue models; patient-derived iPSC cochlear hair cells, hepatocytes, renal-tubule organoids, and granulosa/oocyte-like cells; and isogenic CRISPR-corrected controls.

Evidence assessment and 2023–2024 research context

No new COXPD34-specific patient series was identified for 2023–2024. The most relevant recent advances are field-level: a 24 May 2024 review synthesized how mitoribosome and mitochondrial-translation defects impair OXPHOS and preferentially injure high-energy tissues; a 2024 French cohort of more than 2,000 suspected cases supported broad WES/WGS-based diagnosis; and 2024 patient-fibroblast proteomics illustrated how loss of associated mitoribosomal subunits can help resolve VUS. These developments strengthen the diagnostic framework but do not change COXPD34 treatment or provide disease-specific epidemiology. (rouzier2024primarymitochondrialdisorders pages 1-2, rouzier2024primarymitochondrialdisorders pages 8-11, antolinezfernandez2024molecularpathwaysin pages 1-2)

The evidence hierarchy is therefore: (1) strong human familial segregation plus patient-cell rescue for p.Met184Val; (2) independent human allelic replication with clinical concordance for p.Lys125/p.Arg179His; (3) mechanistic inference for tissue selectivity and ovarian injury; and (4)* no direct evidence for disease-specific drugs, advanced therapies, natural animal disease, or population statistics.

References

(kline2022integralroleof pages 2-4): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(menezes2015mutationinmitochondrial pages 2-3): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(menezes2015mutationinmitochondrial pages 1-2): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(kline2022integralroleof pages 1-2): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(menezes2015mutationinmitochondrial pages 3-4): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(menezes2015mutationinmitochondrial pages 6-7): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(kline2022integralroleof pages 4-5): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(kline2022integralroleof pages 5-8): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(kline2022integralroleof pages 8-9): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(kline2022integralroleof pages 9-10): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(OpenTargets Search: Combined oxidative phosphorylation deficiency 34): Open Targets Query (Combined oxidative phosphorylation deficiency 34, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(webb2020mitochondrialtranslationdefects pages 12-13): Bryn D. Webb, George A. Diaz, and Pankaj Prasun. Mitochondrial translation defects and human disease. Journal of translational genetics and genomics, 4:71-80, May 2020. URL: https://doi.org/10.20517/jtgg.2020.11, doi:10.20517/jtgg.2020.11. This article has 29 citations.
(menezes2015mutationinmitochondrial pages 2-2): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(menezes2015mutationinmitochondrial pages 7-8): Minal J. Menezes, Yiran Guo, Jianguo Zhang, Lisa G. Riley, Sandra T. Cooper, David R. Thorburn, Jiankang Li, Daoyuan Dong, Zhijun Li, Joseph Glessner, Ryan L. Davis, Carolyn M. Sue, Stephen I. Alexander, Susan Arbuckle, Paul Kirwan, Brendan J. Keating, Xun Xu, Hakon Hakonarson, and John Christodoulou. Mutation in mitochondrial ribosomal protein s7 (mrps7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. Human molecular genetics, 24 8:2297-307, Jan 2015. URL: https://doi.org/10.1093/hmg/ddu747, doi:10.1093/hmg/ddu747. This article has 62 citations and is from a domain leading peer-reviewed journal.
(kline2022integralroleof pages 10-12): Brianna L. Kline, Sylvie Jaillard, Katrina M. Bell, Shabnam Bakhshalizadeh, Gorjana Robevska, Jocelyn van den Bergen, Jérôme Dulon, Katie L. Ayers, John Christodoulou, Michel C. Tchan, Philippe Touraine, Andrew H. Sinclair, and Elena J. Tucker. Integral role of the mitochondrial ribosome in supporting ovarian function: mrps7 variants in syndromic premature ovarian insufficiency. Nov 2022. URL: https://doi.org/10.3390/genes13112113, doi:10.3390/genes13112113. This article has 19 citations.
(antolinezfernandez2024molecularpathwaysin pages 1-2): Álvaro Antolínez-Fernández, Paula Esteban-Ramos, Miguel Ángel Fernández-Moreno, and Paula Clemente. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis. Frontiers in Cell and Developmental Biology, May 2024. URL: https://doi.org/10.3389/fcell.2024.1410245, doi:10.3389/fcell.2024.1410245. This article has 18 citations.
(rouzier2024primarymitochondrialdisorders pages 1-2): Cécile Rouzier, Emmanuelle Pion, Annabelle Chaussenot, Céline Bris, Samira Ait‐El‐Mkadem Saadi, Valérie Desquiret‐Dumas, Naïg Gueguen, Konstantina Fragaki, Patrizia Amati‐Bonneau, Giulia Barcia, Pauline Gaignard, Julie Steffann, Alessandra Pennisi, Jean‐Paul Bonnefont, Elise Lebigot, Sylvie Bannwarth, Bruno Francou, Benoit Rucheton, Damien Sternberg, Marie‐Laure Martin‐Negrier, Aurélien Trimouille, Gaëlle Hardy, Stéphane Allouche, Cécile Acquaviva‐Bourdain, Cécile Pagan, Anne‐Sophie Lebre, Pascal Reynier, Mireille Cossee, Shahram Attarian, Véronique Paquis‐Flucklinger, and Vincent Procaccio. Primary mitochondrial disorders and mimics: insights from a large french cohort. Annals of Clinical and Translational Neurology, 11:1478-1491, May 2024. URL: https://doi.org/10.1002/acn3.52062, doi:10.1002/acn3.52062. This article has 16 citations and is from a peer-reviewed journal.
(rouzier2024primarymitochondrialdisorders pages 8-11): Cécile Rouzier, Emmanuelle Pion, Annabelle Chaussenot, Céline Bris, Samira Ait‐El‐Mkadem Saadi, Valérie Desquiret‐Dumas, Naïg Gueguen, Konstantina Fragaki, Patrizia Amati‐Bonneau, Giulia Barcia, Pauline Gaignard, Julie Steffann, Alessandra Pennisi, Jean‐Paul Bonnefont, Elise Lebigot, Sylvie Bannwarth, Bruno Francou, Benoit Rucheton, Damien Sternberg, Marie‐Laure Martin‐Negrier, Aurélien Trimouille, Gaëlle Hardy, Stéphane Allouche, Cécile Acquaviva‐Bourdain, Cécile Pagan, Anne‐Sophie Lebre, Pascal Reynier, Mireille Cossee, Shahram Attarian, Véronique Paquis‐Flucklinger, and Vincent Procaccio. Primary mitochondrial disorders and mimics: insights from a large french cohort. Annals of Clinical and Translational Neurology, 11:1478-1491, May 2024. URL: https://doi.org/10.1002/acn3.52062, doi:10.1002/acn3.52062. This article has 16 citations and is from a peer-reviewed journal.
(antolinezfernandez2024molecularpathwaysin pages 14-15): Álvaro Antolínez-Fernández, Paula Esteban-Ramos, Miguel Ángel Fernández-Moreno, and Paula Clemente. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis. Frontiers in Cell and Developmental Biology, May 2024. URL: https://doi.org/10.3389/fcell.2024.1410245, doi:10.3389/fcell.2024.1410245. This article has 18 citations.

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MONDO:0054741 (3 mentions) - the report calls it "if available"; MONDO calls it combined oxidative phosphorylation deficiency 34

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Combined Oxidative Phosphorylation Deficiency 34: research report

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