MCM3AP-Related Peripheral Neuropathy

Mendelian MONDO:0029131 Pathograph 11 Show in embeddings browser Charcot-Marie-Tooth disease Hereditary motor and sensory neuropathy

MCM3AP-related peripheral neuropathy is an autosomal recessive, childhood-onset sensorimotor neuropathy, usually axonal, with mild to moderate intellectual disability in most affected individuals. It is caused by biallelic variants in MCM3AP, which encodes GANP, the Sac3-domain scaffold subunit of the TREX-2 complex that docks at the nuclear pore and hands newly transcribed messenger ribonucleoproteins to the mRNA export receptor. The disease is therefore a nuclear mRNA export defect presenting as a Charcot-Marie-Tooth phenotype, which is what separates it from the rest of the recessive CMT differential. Nothing in its mechanism concerns myelin proteins, axonal transport motors or mitochondrial dynamics, the usual CMT categories. Two features of the genotype-phenotype relationship are unusually well resolved for a disease this rare, and both follow from where a variant sits in the protein. Variants that deplete GANP produce a more severe phenotype than variants that alter critical residues within the Sac3 mRNA-binding domain, which spare protein levels. And in patient fibroblasts the transcriptome changes are structured by intron content rather than being uniform, with all differentially expressed intronless genes downregulated. That is the most concrete lead available for why long-axoned peripheral neurons are selectively vulnerable, and it is also the point at which the mechanism stops being demonstrated and starts being inferred.

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1
Inheritance
5
Pathophys.
11
Phenotypes
2
Gaps
11
Pathograph
1
Genes
2
Variants
3
Medical Actions
3
Differentials
7
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals are homozygous or compound heterozygous for MCM3AP variants. The reported allele types span missense, splice, frameshift, nonsense and multi-exon deletion.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function."
The disease-defining cohort's genotypes, and the two functional classes the entry's genotype-phenotype section turns on.
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Discussions and Knowledge Gaps

2
Why does a general nuclear mRNA export defect produce a length-dependent peripheral neuropathy rather than a generalized cellular disease?
KNOWLEDGE GAP mcm3ap_length_dependence_mechanism
Attached to
pathophysiology#Length-Dependent Peripheral Axonal Degeneration
GANP and TREX-2 operate in every nucleus, so selective vulnerability of long peripheral axons is the central unexplained feature of this disease. The best available lead is that the transcriptome changes are structured by intron content rather than being uniform, which could concentrate the effect on a particular set of transcripts. But no work connects that transcript set to axonal length, and the original cohort paper presents the export-to-axonal-degeneration link as a suggestion. This entry types that edge as having unknown intermediates for that reason.
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients."
The hedged framing in the disease-defining paper, which is the state of the evidence this gap records.
Is the association between null MCM3AP alleles and worse cognitive and ambulatory outcome real, or an artifact of small cohorts?
KNOWLEDGE GAP mcm3ap_genotype_phenotype_power
Attached to
genetic#MCM3AP
Two separate lines point the same way: patient fibroblasts show that depleting alleles give more severe phenotypes than Sac3-domain alleles, and cohort analysis finds delayed independent walking in the null group. But the cohort's intellectual disability and loss-of-ambulation comparisons did not reach statistical significance, and the authors say so. With fewer than thirty reported individuals in the largest retrospective series, the question is one of power rather than of contradictory evidence, and this entry quotes the non-significant result rather than rounding it up. A later retrospective analysis does report a domain-level correlation, at 100% early-onset symptoms, motor delay and cognitive abnormality for alleles outside the Sac3 domain against 26.7% and 46.7% within it, and that result is curated in the genetic section rather than here. It narrows the gap without closing it: it is a different comparison from the null-versus-Sac3 severity question this discussion is about, it is retrospective over the same small published population, and it reports no significance test.
Show evidence (1 reference)
PMID:32319184 SUPPORT Human Clinical
"The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance."
The explicit statement of non-significance that this gap is about.
⚙

Pathophysiology

5
Biallelic MCM3AP Variants
Missense, splice, frameshift, nonsense and multi-exon deletion alleles in trans or in homozygosity. The functional consequence divides into two classes that behave differently: alleles that deplete GANP protein, and Sac3-domain missense alleles that leave protein levels intact and impair mRNA binding instead.
MCM3AP hgnc:6946 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MCM3AP (hgnc:6946), qualified as loss of function. hgnc:6946 is a gene from the HUGO Gene Nomenclature Committee. ⇓ LOSS OF FUNCTION
Downstream
GANP Depletion or Sac3-Domain Dysfunction
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families."
The original variant identification.
GANP Depletion or Sac3-Domain Dysfunction
The protein-level consequence, and the point at which the two allele classes diverge. Depleting alleles remove the TREX-2 scaffold; Sac3-domain missense alleles leave it present but impaired. The depleting class is associated with the more severe clinical picture, which is the mechanistic basis of the genotype-phenotype correlation.
acetyltransferase activity toward MCM3 GO:0016407 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves acetyltransferase activity toward MCM3, annotated with acetyltransferase activity (GO:0016407). GO:0016407 is a molecular function from the Gene Ontology.
nuclear pore GO:0005643 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear pore (GO:0005643). GO:0005643 is a cellular component from the Gene Ontology.
Downstream
Impaired TREX-2-Mediated Nuclear mRNA Export
Show evidence (2 references)
PMID:32202298 SUPPORT In Vitro
"GANP depletion was associated with more severe phenotypes compared with the Sac3 variants."
Ties the protein-level divergence to clinical severity, which is what makes this node a branch point rather than a single state.
PMID:32954258 SUPPORT INDIRECT Human Clinical
"MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication."
Records GANP's second, non-export function. It is indirect because no reported work shows this activity contributing to the neuropathy, and the entry does not claim it does.
Impaired TREX-2-Mediated Nuclear mRNA Export
Loss of the TREX-2 scaffold impairs handoff of messenger ribonucleoproteins to the export receptor at the nuclear pore. Defects in mRNA export from the nucleus were already linked to neurodegenerative disease before this gene was implicated, which is the general context that made the finding interpretable.
mRNA export from nucleus GO:0006406 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mRNA export from nucleus (GO:0006406). GO:0006406 is a biological process from the Gene Ontology. ↓ DECREASED
nuclear pore GO:0005643 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear pore (GO:0005643). GO:0005643 is a cellular component from the Gene Ontology.
Downstream
Intron-Content-Dependent Transcriptome Alteration
Show evidence (2 references)
PMID:28633435 SUPPORT Human Clinical
"Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders."
The prior context that makes an export defect a plausible neurodegenerative mechanism.
PMID:32202298 SUPPORT In Vitro
"Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability."
States the export-scaffold role and the disease it causes in one sentence.
Intron-Content-Dependent Transcriptome Alteration
The export defect does not perturb the transcriptome uniformly. In patient fibroblasts every differentially expressed intronless gene was downregulated, and one of them is ATXN7L3B, which itself couples mRNA export to transcription activation through the TREX-2 and SAGA complexes. That makes the perturbation partly self-reinforcing, and it is the most specific available account of why a general export defect should hit some cells harder than others.
mRNA transport GO:0051028 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mRNA transport (GO:0051028). GO:0051028 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Length-Dependent Peripheral Axonal Degeneration
Show evidence (1 reference)
PMID:32202298 SUPPORT In Vitro
"For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes."
The specific finding, including the feedback relationship the description turns on.
Length-Dependent Peripheral Axonal Degeneration
Degeneration of long peripheral motor and sensory axons, confirmed on electrophysiology and sural nerve biopsy as an axonal sensorimotor neuropathy in most patients. A minority have demyelinating features instead, including one of the five original families, so the axonal picture is predominant rather than exclusive.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
peripheral nervous system UBERON:0000010 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in peripheral nervous system (UBERON:0000010). UBERON:0000010 is an anatomical location from the Uberon multi-species anatomy ontology. sural nerve UBERON:0015488 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in sural nerve (UBERON:0015488). UBERON:0015488 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Distal Muscle Weakness
Distal Sensory Impairment
Show evidence (2 references)
PMID:32202298 SUPPORT Human Clinical
"Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy, whereas some patients have signs of demyelination."
The two investigations that establish the axonal character, and the acknowledged demyelinating minority.
PMID:28633435 SUPPORT Human Clinical
"The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy."
The four-to-one split between axonal and demyelinating presentations in the original families.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MCM3AP-Related Peripheral Neuropathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Eye 1
Ptosis OCCASIONAL HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32954258 SUPPORT Human Clinical
"Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases"
Ptosis reported as an occasional accompaniment.
Limbs 1
Pes Cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot deformity, annotated with Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"characteristic claw hands and foot deformities"
Foot deformity among the reported features. The source names the deformity generically, so the specific pes cavus term carries the disease-typical form in preferred_term.
Musculoskeletal 2
Distal Muscle Weakness VERY_FREQUENT HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as course progressive. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"causes distal motor impairment and gait difficulties, often resulting in wheelchair dependency and in difficulties using proximal limbs"
The motor phenotype and its progression.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"characteristic claw hands and foot deformities and scoliosis"
Scoliosis listed among the additional skeletal features.
Nervous System 7
Peripheral Axonal Neuropathy VERY_FREQUENT HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral axonal neuropathy (HP:0003477), qualified as course progressive. HP:0003477 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy."
The presentation across the five original families.
Intellectual Disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild to moderate intellectual disability, annotated with Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28633435 SUPPORT Human Clinical
"Mild to moderate intellectual disability was present in seven of nine affected individuals."
The proportion in the original cohort, seven of nine.
PMID:32202298 SUPPORT Human Clinical
"Most affected individuals have impaired intellectual development or learning difficulties, although some have normal cognition."
Confirms that cognition is spared in a minority, which is why this is not curated as an obligatory feature.
Distal Sensory Impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy"
The sensorimotor character established by nerve conduction studies and biopsy.
Loss of Ambulation FREQUENT HP:0002505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wheelchair dependency, annotated with Loss of ambulation (HP:0002505). HP:0002505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"often resulting in wheelchair dependency"
The reported outcome.
Motor Delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed independent walking, annotated with Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32319184 SUPPORT Human Clinical
"affected individuals with null mutations presented with delayed independent walking"
Ties the motor delay specifically to the null allele group.
Fasciculations VERY_RARE HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widespread fasciculations, annotated with Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41819534 SUPPORT Human Clinical
"Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities."
The examination finding itself, in the single reported patient.
PMID:41819534 SUPPORT Human Clinical
"To date, anterior horn cell involvement has not been documented in association with MCM3AP-related disorders."
The authors' own statement that this presentation is new, which is why the frequency band is the lowest available.
Areflexia OCCASIONAL HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized areflexia, annotated with Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41819534 SUPPORT Human Clinical
"Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities."
The examination finding. The same sentence supports the fasciculation phenotype, which is why both are curated from one observation in one patient rather than presented as independent findings.
🧬

Genetic Associations

1
MCM3AP (MCM3AP encodes GANP, the scaffold subunit of the TREX-2 nuclear mRNA export complex. Biallelic hypomorphic or loss-of-function variants cause childhood-onset recessive Charcot-Marie-Tooth neuropathy with or without impaired intellectual development.)
Gene: MCM3AP hgnc:6946 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MCM3AP (hgnc:6946). hgnc:6946 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability."
The statement establishing the gene-disease relationship, and the multi-centre ascertainment behind it.
Variants (2)
MCM3AP Sac3-domain missense variants Pathogenic
Variants altering critical residues within the Sac3 mRNA-binding domain do not deplete GANP, and are associated with a milder phenotype than the depleting alleles. This is the structural basis of the reported genotype-phenotype correlation.
Show evidence (2 references)
PMID:32202298 SUPPORT In Vitro
"our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain"
Measured protein levels in patient fibroblasts separating the two allele classes.
PMID:39228414 SUPPORT Human Clinical
"all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities)"
The quantitative form of the domain correlation, which is what makes Sac3-domain variants a distinct class rather than a structural conjecture. Retrospective over the published population and reported without a significance test, so it is curated as the observed proportions rather than as a settled effect size.
MCM3AP null and depleting variants Pathogenic
Splice, frameshift, nonsense and deletion alleles that reduce GANP protein. In cohort analysis these are associated with delayed independent walking, and with a numerically higher rate of intellectual disability and loss of ambulation.
Show evidence (2 references)
PMID:32319184 SUPPORT Human Clinical
"Genotype-phenotype correlation analysis indicated that affected individuals with null mutations presented with delayed independent walking."
The one genotype-phenotype association this cohort reports as established.
PMID:32319184 SUPPORT INDIRECT Human Clinical
"The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance."
A trend the authors explicitly report as not statistically significant, quoted here so the entry does not overstate it. It is indirect because the association is suggested rather than demonstrated.
💊

Medical Actions

3
Rehabilitation and Physical Therapy
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Platform: Behavioral / lifestyle
There is no disease-modifying therapy. Management is supportive and rehabilitative, directed at the progressive distal weakness and the consequences of loss of ambulation.
Mechanism Target:
MODULATES Distal Muscle Weakness — Supportive rather than mechanism-directed. Nothing in the cited literature evaluates rehabilitation in this disorder specifically.
Show evidence (2 references)
PMID:32202298 SUPPORT Human Clinical
"This childhood-onset neurologic syndrome is progressive and causes distal motor impairment and gait difficulties, often resulting in wheelchair dependency"
The progressive motor impairment that rehabilitation addresses. The cited work characterizes the course and does not evaluate the intervention.
PMID:39228414 SUPPORT Human Clinical
"Additionally, we elaborate on the importance of rehabilitation intervention."
The only statement in the cached literature that recommends rehabilitation for this disease rather than merely describing the impairment it would address. Still not an evaluation of the intervention.
Orthopedic Management of Foot and Spinal Deformity
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Platform: Surgery
Orthotic and surgical management of the foot deformity and scoliosis that accompany the neuropathy, as in Charcot-Marie-Tooth disease generally.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"characteristic claw hands and foot deformities and scoliosis"
The deformities this management addresses. No disorder-specific outcome evidence exists.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal recessive recurrence counselling. The genotype-phenotype correlation is relevant to prognostic discussion, though the only association reported as established rather than as a trend is delayed independent walking in the null group.
Show evidence (1 reference)
PMID:32319184 SUPPORT Human Clinical
"Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients."
The authors' own statement of the counselling application.
🔬

Diagnosis

3
Whole-exome sequencing with copy-number analysis
Exome sequencing finds the point and splice variants; copy-number analysis is needed as well, because multi-exon deletions are part of the reported allele spectrum and are invisible to sequencing alone.
Show evidence (1 reference)
PMID:39228414 SUPPORT Human Clinical
"Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family"
The combined assay approach used to reach a molecular diagnosis in this family.
Splicing analysis for candidate splice variants
A splice-site variant needs functional confirmation, because the consequence, and therefore whether the allele is null, is not predictable from the genomic change. In the reported case reverse-transcription PCR showed an aberrant transcript eliminated by nonsense-mediated decay.
Show evidence (1 reference)
PMID:32319184 SUPPORT Human Clinical
"Functional studies showed that c.5634-1G>T led to splicing defect and aberrant transcript eliminated by nonsense-mediated mRNA decay."
The functional work that established this allele as null, which is what places a patient in the more severe genotype group.
Nerve conduction studies and sural nerve biopsy
Electrophysiology and biopsy establish whether the neuropathy is axonal or demyelinating. Both patterns occur, so the result narrows the differential without settling it.
Show evidence (1 reference)
PMID:32202298 SUPPORT Human Clinical
"Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy, whereas some patients have signs of demyelination."
What the two investigations show and the limit of what they settle.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from MCM3AP-Related Peripheral Neuropathy:

Other recessive Charcot-Marie-Tooth neuropathies
Overlapping Features Clinically this presents as recessive childhood-onset CMT and is indistinguishable from the rest of that group on examination. What separates it is the mechanism: a nuclear mRNA export defect rather than a myelin, axonal transport or mitochondrial lesion. That distinction is only accessible through sequencing.
Show evidence (1 reference)
PMID:28633435 SUPPORT Human Clinical
"The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability."
Places the disorder inside the recessive CMT group that this differential covers.
Multiple sclerosis
Overlapping Features Not only a mimic but a documented co-occurrence. Three affected members of one family homozygous for a Sac3-domain variant had CMT together with multiple sclerosis, which the authors propose should put MCM3AP into consideration when the two present together.
Show evidence (2 references)
PMID:32954258 SUPPORT Human Clinical
"we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause"
The reported co-occurrence in a single family.
PMID:32954258 SUPPORT Human Clinical
"MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis"
The authors' recommendation, which is what makes this a differential rather than an incidental observation.
Motor neuronopathy and anterior horn cell disease
Overlapping Features A single reported patient presented with a motor neuronopathy phenotype and widespread fasciculations, a picture that would ordinarily point away from a peripheral neuropathy gene.
Show evidence (1 reference)
PMID:41819534 SUPPORT Human Clinical
"This case extends the phenotypic spectrum of MCM3AP-related disorders to include a slowly progressive, non-syndromic motor neuronopathy with electrophysiological evidence of active denervation and distinctive MRI findings."
The authors' conclusion rather than their stated aim, so the claim rests on what the case showed rather than on what the study set out to do.
{ }

Source YAML

click to show 
name: MCM3AP-Related Peripheral Neuropathy
creation_date: "2026-09-05T10:00:00Z"
category: Mendelian
synonyms:
- PNRIID
- peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
- MCM3AP-related Charcot-Marie-Tooth disease
- GANP-related neuropathy
description: >-
  MCM3AP-related peripheral neuropathy is an autosomal recessive, childhood-onset
  sensorimotor neuropathy, usually axonal, with mild to moderate intellectual
  disability in most affected individuals. It is caused by biallelic variants in
  MCM3AP, which encodes GANP, the Sac3-domain scaffold subunit of the TREX-2
  complex that docks at the nuclear pore and hands newly transcribed messenger
  ribonucleoproteins to the mRNA export receptor.

  The disease is therefore a nuclear mRNA export defect presenting as a
  Charcot-Marie-Tooth phenotype, which is what separates it from the rest of the
  recessive CMT differential. Nothing in its mechanism concerns myelin proteins,
  axonal transport motors or mitochondrial dynamics, the usual CMT categories.

  Two features of the genotype-phenotype relationship are unusually well
  resolved for a disease this rare, and both follow from where a variant sits in
  the protein. Variants that deplete GANP produce a more severe phenotype than
  variants that alter critical residues within the Sac3 mRNA-binding domain,
  which spare protein levels. And in patient fibroblasts the transcriptome
  changes are structured by intron content rather than being uniform, with all
  differentially expressed intronless genes downregulated. That is the most
  concrete lead available for why long-axoned peripheral neurons are selectively
  vulnerable, and it is also the point at which the mechanism stops being
  demonstrated and starts being inferred.
disease_term:
  preferred_term: MCM3AP-related peripheral neuropathy
  term:
    id: MONDO:0029131
    label: peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
parents:
- Charcot-Marie-Tooth disease
- Hereditary motor and sensory neuropathy
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for MCM3AP
    variants. The reported allele types span missense, splice, frameshift,
    nonsense and multi-exon deletion.
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function."
    explanation: The disease-defining cohort's genotypes, and the two functional classes the entry's genotype-phenotype section turns on.
genetic:
- name: MCM3AP
  gene_term:
    preferred_term: MCM3AP
    term:
      id: hgnc:6946
      label: MCM3AP
  association: >-
    MCM3AP encodes GANP, the scaffold subunit of the TREX-2 nuclear mRNA export
    complex. Biallelic hypomorphic or loss-of-function variants cause
    childhood-onset recessive Charcot-Marie-Tooth neuropathy with or without
    impaired intellectual development.
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability."
    explanation: The statement establishing the gene-disease relationship, and the multi-centre ascertainment behind it.
  variants:
  - name: MCM3AP Sac3-domain missense variants
    description: >-
      Variants altering critical residues within the Sac3 mRNA-binding domain do
      not deplete GANP, and are associated with a milder phenotype than the
      depleting alleles. This is the structural basis of the reported
      genotype-phenotype correlation.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32202298
      reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain"
      explanation: Measured protein levels in patient fibroblasts separating the two allele classes.
    - reference: PMID:39228414
      reference_title: "Identification of biallelic mutations in MCM3AP and comprehensive literature analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities)"
      explanation: >-
        The quantitative form of the domain correlation, which is what makes
        Sac3-domain variants a distinct class rather than a structural
        conjecture. Retrospective over the published population and reported
        without a significance test, so it is curated as the observed
        proportions rather than as a settled effect size.
  - name: MCM3AP null and depleting variants
    description: >-
      Splice, frameshift, nonsense and deletion alleles that reduce GANP
      protein. In cohort analysis these are associated with delayed independent
      walking, and with a numerically higher rate of intellectual disability and
      loss of ambulation.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32319184
      reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genotype-phenotype correlation analysis indicated that affected individuals with null mutations presented with delayed independent walking."
      explanation: The one genotype-phenotype association this cohort reports as established.
    - reference: PMID:32319184
      reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance."
      explanation: A trend the authors explicitly report as not statistically significant, quoted here so the entry does not overstate it. It is indirect because the association is suggested rather than demonstrated.
pathophysiology:
- name: Biallelic MCM3AP Variants
  biological_scale: MOLECULAR
  description: >-
    Missense, splice, frameshift, nonsense and multi-exon deletion alleles in
    trans or in homozygosity. The functional consequence divides into two
    classes that behave differently: alleles that deplete GANP protein, and
    Sac3-domain missense alleles that leave protein levels intact and impair
    mRNA binding instead.
  gene:
    preferred_term: MCM3AP
    modifier: LOSS_OF_FUNCTION
    term:
      id: hgnc:6946
      label: MCM3AP
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families."
    explanation: The original variant identification.
  downstream:
  - target: GANP Depletion or Sac3-Domain Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28633435
      reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP."
      explanation: Direct measurement of the protein consequence in patient cells.
- name: GANP Depletion or Sac3-Domain Dysfunction
  biological_scale: MOLECULAR
  description: >-
    The protein-level consequence, and the point at which the two allele classes
    diverge. Depleting alleles remove the TREX-2 scaffold; Sac3-domain missense
    alleles leave it present but impaired. The depleting class is associated with
    the more severe clinical picture, which is the mechanistic basis of the
    genotype-phenotype correlation.
  molecular_functions:
  - preferred_term: acetyltransferase activity toward MCM3
    term:
      id: GO:0016407
      label: acetyltransferase activity
  cellular_components:
  - preferred_term: nuclear pore
    term:
      id: GO:0005643
      label: nuclear pore
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "GANP depletion was associated with more severe phenotypes compared with the Sac3 variants."
    explanation: Ties the protein-level divergence to clinical severity, which is what makes this node a branch point rather than a single state.
  - reference: PMID:32954258
    reference_title: "Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication."
    explanation: Records GANP's second, non-export function. It is indirect because no reported work shows this activity contributing to the neuropathy, and the entry does not claim it does.
  downstream:
  - target: Impaired TREX-2-Mediated Nuclear mRNA Export
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28633435
      reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "GANP has been described to function as an mRNA export factor"
      explanation: >-
        The export function whose loss this edge asserts. Graded OTHER because
        the clause is the paper's background summary of established molecular
        function rather than a result of the clinical study it introduces.
    - reference: PMID:28633435
      reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "to suppress TDP-43-mediated motor neuron degeneration in flies"
      explanation: >-
        The fly result that first connected GANP to motor neuron degeneration.
        Split from the export clause because the two halves of that sentence are
        different kinds of evidence, and indirect because it is a Drosophila
        TDP-43 model rather than this disease.
- name: Impaired TREX-2-Mediated Nuclear mRNA Export
  biological_scale: CELLULAR
  description: >-
    Loss of the TREX-2 scaffold impairs handoff of messenger ribonucleoproteins
    to the export receptor at the nuclear pore. Defects in mRNA export from the
    nucleus were already linked to neurodegenerative disease before this gene
    was implicated, which is the general context that made the finding
    interpretable.
  biological_processes:
  - preferred_term: mRNA export from nucleus
    modifier: DECREASED
    term:
      id: GO:0006406
      label: mRNA export from nucleus
  cellular_components:
  - preferred_term: nuclear pore
    term:
      id: GO:0005643
      label: nuclear pore
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders."
    explanation: The prior context that makes an export defect a plausible neurodegenerative mechanism.
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability."
    explanation: States the export-scaffold role and the disease it causes in one sentence.
  downstream:
  - target: Intron-Content-Dependent Transcriptome Alteration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32202298
      reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression."
      explanation: The measured transcriptome consequence in patient cells.
- name: Intron-Content-Dependent Transcriptome Alteration
  biological_scale: CELLULAR
  description: >-
    The export defect does not perturb the transcriptome uniformly. In patient
    fibroblasts every differentially expressed intronless gene was
    downregulated, and one of them is ATXN7L3B, which itself couples mRNA export
    to transcription activation through the TREX-2 and SAGA complexes. That
    makes the perturbation partly self-reinforcing, and it is the most specific
    available account of why a general export defect should hit some cells
    harder than others.
  biological_processes:
  - preferred_term: mRNA transport
    modifier: ABNORMAL
    term:
      id: GO:0051028
      label: mRNA transport
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes."
    explanation: The specific finding, including the feedback relationship the description turns on.
  downstream:
  - target: Length-Dependent Peripheral Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28633435
      reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients."
      explanation: The authors present the link between the export defect and axonal degeneration as a suggested potential mechanism, and this entry types the edge accordingly rather than asserting it.
- name: Length-Dependent Peripheral Axonal Degeneration
  biological_scale: TISSUE
  description: >-
    Degeneration of long peripheral motor and sensory axons, confirmed on
    electrophysiology and sural nerve biopsy as an axonal sensorimotor
    neuropathy in most patients. A minority have demyelinating features instead,
    including one of the five original families, so the axonal picture is
    predominant rather than exclusive.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy, whereas some patients have signs of demyelination."
    explanation: The two investigations that establish the axonal character, and the acknowledged demyelinating minority.
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy."
    explanation: The four-to-one split between axonal and demyelinating presentations in the original families.
  downstream:
  - target: Distal Muscle Weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32202298
      reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This childhood-onset neurologic syndrome is progressive and causes distal motor impairment and gait difficulties, often resulting in wheelchair dependency and in difficulties using proximal limbs."
      explanation: The clinical course produced by the axonal degeneration, including its progression to proximal involvement.
  - target: Distal Sensory Impairment
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28633435
      reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy"
      explanation: >-
        Indirect by construction. The quote establishes the Charcot-Marie-Tooth
        diagnosis, and the sensory arm follows from that diagnosis being
        sensorimotor by definition rather than from any sensory measurement in
        the quoted sentence.
phenotypes:
- name: Peripheral Axonal Neuropathy
  category: Neurological
  description: >-
    The defining feature. Childhood-onset, progressive, and axonal in most
    patients, with a demyelinating minority.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy."
    explanation: The presentation across the five original families.
- name: Intellectual Disability
  category: Neurodevelopmental
  description: >-
    Mild to moderate, and present in most but not all patients. The "with or
    without" in the OMIM phenotype name is doing real work: some individuals
    have normal cognition.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Mild to moderate intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild to moderate intellectual disability was present in seven of nine affected individuals."
    explanation: The proportion in the original cohort, seven of nine.
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals have impaired intellectual development or learning difficulties, although some have normal cognition."
    explanation: Confirms that cognition is spared in a minority, which is why this is not curated as an obligatory feature.
- name: Distal Muscle Weakness
  category: Musculoskeletal
  description: >-
    Distal motor impairment with gait difficulty, progressing in many patients
    to wheelchair dependency and to proximal limb involvement.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "causes distal motor impairment and gait difficulties, often resulting in wheelchair dependency and in difficulties using proximal limbs"
    explanation: The motor phenotype and its progression.
- name: Distal Sensory Impairment
  category: Neurological
  description: >-
    The sensory half of the sensorimotor neuropathy.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy"
    explanation: The sensorimotor character established by nerve conduction studies and biopsy.
- name: Loss of Ambulation
  category: Musculoskeletal
  description: >-
    Wheelchair dependency is a frequent outcome of the progressive motor
    impairment.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Wheelchair dependency
    term:
      id: HP:0002505
      label: Loss of ambulation
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "often resulting in wheelchair dependency"
    explanation: The reported outcome.
- name: Motor Delay
  category: Neurodevelopmental
  description: >-
    Delayed independent walking, reported specifically in patients carrying null
    alleles.
  phenotype_term:
    preferred_term: Delayed independent walking
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:32319184
    reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affected individuals with null mutations presented with delayed independent walking"
    explanation: Ties the motor delay specifically to the null allele group.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Part of the reported additional feature set alongside foot and hand
    deformity.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic claw hands and foot deformities and scoliosis"
    explanation: Scoliosis listed among the additional skeletal features.
- name: Pes Cavus
  category: Musculoskeletal
  description: >-
    Foot deformity of the type characteristic of Charcot-Marie-Tooth disease.
  phenotype_term:
    preferred_term: Foot deformity
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic claw hands and foot deformities"
    explanation: Foot deformity among the reported features. The source names the deformity generically, so the specific pes cavus term carries the disease-typical form in preferred_term.
- name: Ptosis
  category: Ophthalmological
  description: >-
    Reported in some patients, alongside eye movement abnormalities.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:32954258
    reference_title: "Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases"
    explanation: Ptosis reported as an occasional accompaniment.
- name: Fasciculations
  category: Neurological
  description: >-
    Widespread fasciculations in a patient with an anterior horn cell
    presentation. This is a single report and the authors state that anterior
    horn involvement had not previously been documented for this gene.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Widespread fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:41819534
    reference_title: "Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities."
    explanation: The examination finding itself, in the single reported patient.
  - reference: PMID:41819534
    reference_title: "Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, anterior horn cell involvement has not been documented in association with MCM3AP-related disorders."
    explanation: The authors' own statement that this presentation is new, which is why the frequency band is the lowest available.
- name: Areflexia
  category: Neurological
  description: >-
    Generalized areflexia, documented on examination in the motor-neuronopathy
    case. Loss of reflexes is expected in a length-dependent sensorimotor
    neuropathy, but the cached literature records it explicitly only in this one
    patient, so the frequency band reflects what is documented rather than what
    the disease mechanism would predict.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Generalized areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:41819534
    reference_title: "Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities."
    explanation: >-
      The examination finding. The same sentence supports the fasciculation
      phenotype, which is why both are curated from one observation in one
      patient rather than presented as independent findings.
treatments:
- name: Rehabilitation and Physical Therapy
  description: >-
    There is no disease-modifying therapy. Management is supportive and
    rehabilitative, directed at the progressive distal weakness and the
    consequences of loss of ambulation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This childhood-onset neurologic syndrome is progressive and causes distal motor impairment and gait difficulties, often resulting in wheelchair dependency"
    explanation: The progressive motor impairment that rehabilitation addresses. The cited work characterizes the course and does not evaluate the intervention.
  - reference: PMID:39228414
    reference_title: "Identification of biallelic mutations in MCM3AP and comprehensive literature analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we elaborate on the importance of rehabilitation intervention."
    explanation: >-
      The only statement in the cached literature that recommends rehabilitation
      for this disease rather than merely describing the impairment it would
      address. Still not an evaluation of the intervention.
  target_mechanisms:
  - target: Distal Muscle Weakness
    treatment_effect: MODULATES
    description: >-
      Supportive rather than mechanism-directed. Nothing in the cited literature
      evaluates rehabilitation in this disorder specifically.
- name: Orthopedic Management of Foot and Spinal Deformity
  description: >-
    Orthotic and surgical management of the foot deformity and scoliosis that
    accompany the neuropathy, as in Charcot-Marie-Tooth disease generally.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic claw hands and foot deformities and scoliosis"
    explanation: The deformities this management addresses. No disorder-specific outcome evidence exists.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence counselling. The genotype-phenotype
    correlation is relevant to prognostic discussion, though the only
    association reported as established rather than as a trend is delayed
    independent walking in the null group.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32319184
    reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients."
    explanation: The authors' own statement of the counselling application.
diagnosis:
- name: Whole-exome sequencing with copy-number analysis
  description: >-
    Exome sequencing finds the point and splice variants; copy-number analysis
    is needed as well, because multi-exon deletions are part of the reported
    allele spectrum and are invisible to sequencing alone.
  evidence:
  - reference: PMID:39228414
    reference_title: "Identification of biallelic mutations in MCM3AP and comprehensive literature analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family"
    explanation: The combined assay approach used to reach a molecular diagnosis in this family.
- name: Splicing analysis for candidate splice variants
  description: >-
    A splice-site variant needs functional confirmation, because the
    consequence, and therefore whether the allele is null, is not predictable
    from the genomic change. In the reported case reverse-transcription PCR
    showed an aberrant transcript eliminated by nonsense-mediated decay.
  evidence:
  - reference: PMID:32319184
    reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional studies showed that c.5634-1G>T led to splicing defect and aberrant transcript eliminated by nonsense-mediated mRNA decay."
    explanation: The functional work that established this allele as null, which is what places a patient in the more severe genotype group.
- name: Nerve conduction studies and sural nerve biopsy
  description: >-
    Electrophysiology and biopsy establish whether the neuropathy is axonal or
    demyelinating. Both patterns occur, so the result narrows the differential
    without settling it.
  evidence:
  - reference: PMID:32202298
    reference_title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiological testing and sural nerve biopsy are most compatible with an axonal sensorimotor neuropathy, whereas some patients have signs of demyelination."
    explanation: What the two investigations show and the limit of what they settle.
differential_diagnoses:
- name: Other recessive Charcot-Marie-Tooth neuropathies
  description: >-
    Clinically this presents as recessive childhood-onset CMT and is
    indistinguishable from the rest of that group on examination. What separates
    it is the mechanism: a nuclear mRNA export defect rather than a myelin,
    axonal transport or mitochondrial lesion. That distinction is only
    accessible through sequencing.
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability."
    explanation: Places the disorder inside the recessive CMT group that this differential covers.
- name: Multiple sclerosis
  description: >-
    Not only a mimic but a documented co-occurrence. Three affected members of
    one family homozygous for a Sac3-domain variant had CMT together with
    multiple sclerosis, which the authors propose should put MCM3AP into
    consideration when the two present together.
  evidence:
  - reference: PMID:32954258
    reference_title: "Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause"
    explanation: The reported co-occurrence in a single family.
  - reference: PMID:32954258
    reference_title: "Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis"
    explanation: The authors' recommendation, which is what makes this a differential rather than an incidental observation.
- name: Motor neuronopathy and anterior horn cell disease
  description: >-
    A single reported patient presented with a motor neuronopathy phenotype and
    widespread fasciculations, a picture that would ordinarily point away from a
    peripheral neuropathy gene.
  evidence:
  - reference: PMID:41819534
    reference_title: "Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case extends the phenotypic spectrum of MCM3AP-related disorders to include a slowly progressive, non-syndromic motor neuronopathy with electrophysiological evidence of active denervation and distinctive MRI findings."
    explanation: >-
      The authors' conclusion rather than their stated aim, so the claim rests
      on what the case showed rather than on what the study set out to do.
discussions:
- discussion_id: mcm3ap_length_dependence_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does a general nuclear mRNA export defect produce a length-dependent
    peripheral neuropathy rather than a generalized cellular disease?
  attaches_to:
  - pathophysiology#Length-Dependent Peripheral Axonal Degeneration
  rationale: >-
    GANP and TREX-2 operate in every nucleus, so selective vulnerability of long
    peripheral axons is the central unexplained feature of this disease. The
    best available lead is that the transcriptome changes are structured by
    intron content rather than being uniform, which could concentrate the effect
    on a particular set of transcripts. But no work connects that transcript set
    to axonal length, and the original cohort paper presents the export-to-axonal-degeneration
    link as a suggestion. This entry types that edge as having unknown
    intermediates for that reason.
  evidence:
  - reference: PMID:28633435
    reference_title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients."
    explanation: The hedged framing in the disease-defining paper, which is the state of the evidence this gap records.
- discussion_id: mcm3ap_genotype_phenotype_power
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the association between null MCM3AP alleles and worse cognitive and
    ambulatory outcome real, or an artifact of small cohorts?
  attaches_to:
  - genetic#MCM3AP
  rationale: >-
    Two separate lines point the same way: patient fibroblasts show that
    depleting alleles give more severe phenotypes than Sac3-domain alleles, and
    cohort analysis finds delayed independent walking in the null group. But the
    cohort's intellectual disability and loss-of-ambulation comparisons did not
    reach statistical significance, and the authors say so. With fewer than
    thirty reported individuals in the largest retrospective series, the
    question is one of power rather than of contradictory evidence, and this
    entry quotes the non-significant result rather than rounding it up.

    A later retrospective analysis does report a domain-level correlation, at
    100% early-onset symptoms, motor delay and cognitive abnormality for alleles
    outside the Sac3 domain against 26.7% and 46.7% within it, and that result
    is curated in the genetic section rather than here. It narrows the gap
    without closing it: it is a different comparison from the null-versus-Sac3
    severity question this discussion is about, it is retrospective over the
    same small published population, and it reports no significance test.
  evidence:
  - reference: PMID:32319184
    reference_title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance."
    explanation: The explicit statement of non-significance that this gap is about.
references:
- reference: PMID:28633435
  title: "MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability."
- reference: PMID:32202298
  title: "Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content."
- reference: PMID:32319184
  title: "Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease."
- reference: PMID:32954258
  title: "Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP."
- reference: PMID:39228414
  title: "Identification of biallelic mutations in MCM3AP and comprehensive literature analysis."
- reference: PMID:41819534
  title: "Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights."
- reference: PMID:28969388
  title: "Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation."
notes: >-
  Deep-research provenance. Curated alongside an OpenScientist report
  (research/MCM3AP-Related_Peripheral_Neuropathy-deep-research-openscientist.md).
  All 18 of its references resolved, and its causal chain matched the one built
  here from the primary literature.

  Its quote validation flagged two references whose attributed quotes could not
  be found in the record: PMID:23652018 and PMID:27235683. Neither is cited in
  this entry, and no quoted material from either was reused.

  PMID:28969388 has no abstract available in PubMed, so it carries no evidence
  item and appears in the reference block only. It is kept there because it is
  one of the concurrent papers that established the gene-disease relationship.

  Where the mechanism stops being demonstrated. The chain from biallelic
  variants through GANP depletion to impaired mRNA export is measured. The step
  from impaired export to length-dependent axonal degeneration is not: the
  disease-defining paper presents it as a suggested potential mechanism, and
  that edge is typed INDIRECT_UNKNOWN_INTERMEDIATES with a knowledge gap
  attached rather than being asserted. The report's own chain labels the same
  step "(Inferred.)", which agrees.

  The R-loop and transcription-coupled genome instability branch that the report
  describes is not curated as a pathophysiology node. The report itself marks
  the contribution of that branch to the neuropathy as inferred, and the sources
  cached here do not carry a quotable statement connecting R-loops to this
  disease, so a node would assert more than the evidence supports.

  GANP's acetyltransferase activity is recorded on the protein-level node with
  directness INDIRECT and an explanation stating that no reported work shows it
  contributing to the neuropathy. It is included because it is what a reader
  encountering the gene's other literature will need to place.
📚

References & Deep Research

References

7
PMID:28633435
MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.
No top-level findings curated for this source.
PMID:32202298
Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.
No top-level findings curated for this source.
PMID:32319184
Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease.
No top-level findings curated for this source.
PMID:32954258
Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP.
No top-level findings curated for this source.
PMID:39228414
Identification of biallelic mutations in MCM3AP and comprehensive literature analysis.
No top-level findings curated for this source.
PMID:41819534
Motor Neuronopathy With Widespread Fasciculations in MCM3AP-Related Disorder: Clinical and Muscle MRI Insights.
No top-level findings curated for this source.
PMID:28969388
Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation.
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 (2)

Record notes

Deep-research provenance. Curated alongside an OpenScientist report (research/MCM3AP-Related_Peripheral_Neuropathy-deep-research-openscientist.md). All 18 of its references resolved, and its causal chain matched the one built here from the primary literature. Its quote validation flagged two references whose attributed quotes could not be found in the record: PMID:23652018 and PMID:27235683. Neither is cited in this entry, and no quoted material from either was reused. PMID:28969388 has no abstract available in PubMed, so it carries no evidence item and appears in the reference block only. It is kept there because it is one of the concurrent papers that established the gene-disease relationship. Where the mechanism stops being demonstrated. The chain from biallelic variants through GANP depletion to impaired mRNA export is measured. The step from impaired export to length-dependent axonal degeneration is not: the disease-defining paper presents it as a suggested potential mechanism, and that edge is typed INDIRECT_UNKNOWN_INTERMEDIATES with a knowledge gap attached rather than being asserted. The report's own chain labels the same step "(Inferred.)", which agrees. The R-loop and transcription-coupled genome instability branch that the report describes is not curated as a pathophysiology node. The report itself marks the contribution of that branch to the neuropathy as inferred, and the sources cached here do not carry a quotable statement connecting R-loops to this disease, so a node would assert more than the evidence supports. GANP's acetyltransferase activity is recorded on the protein-level node with directness INDIRECT and an explanation stating that no reported work shows it contributing to the neuropathy. It is included because it is what a reader encountering the gene's other literature will need to place.

Create: MCM3AP-Related Peripheral Neuropathy (PNRIID, GANP/TREX-2) · 2026-09-05T15:17:04Z · View source

New kb/disorders entry for PNRIID (MONDO:0029131), claimed via issue #11108. Curated as a nuclear mRNA export defect presenting as recessive Charcot-Marie-Tooth neuropathy, which is what distinguishes it from the rest of the recessive CMT differential: nothing in the mechanism concerns myelin proteins, axonal transport motors or mitochondrial dynamics. Chain runs biallelic MCM3AP variants to GANP depletion or Sac3-domain dysfunction to impaired TREX-2-mediated export to intron-content-dependent transcriptome alteration to length-dependent axonal degeneration. The last edge is typed INDIRECT_UNKNOWN_INTERMEDIATES with an attached KNOWLEDGE_GAP, because the disease-defining paper presents the export-to-degeneration link as a suggested potential mechanism and the report's own chain labels the same step inferred. Ten HPO-bound phenotypes, two allele classes with the fibroblast protein-level evidence that separates them, three treatments, three diagnostic entries, three differentials, two KNOWLEDGE_GAP discussions. The genotype-phenotype gap quotes the cohort's own statement that the intellectual disability and loss-of-ambulation comparison failed to reach statistical significance, rather than rounding a trend up to a finding. Deep research: OpenScientist report committed; 18/18 references resolved. Its quote validation flagged PMID:23652018 and PMID:27235683 as carrying unsupported quotes; neither is cited here and no quoted material from either was reused. PMID:28969388 has no PubMed abstract so it is reference-block only. The report's R-loop and transcription-coupled genome instability branch is deliberately not curated as a node, because the report marks its contribution to the neuropathy as inferred and no cached source carries a quotable statement connecting R-loops to this disease. Validation: schema pass, term validation pass, 43/43 snippets verified, check-entity-refs / check-causal-targets / check-duplicate-keys / check-enum-values clean.

OpenScientist ▸
MCM3AP-Related Peripheral Neuropathy — Comprehensive Disease Report
openscientist-autonomous 14 citations 2026-09-05T15:00:54.703471

MCM3AP-Related Peripheral Neuropathy — Comprehensive Disease Report

Disease Name: MCM3AP-Related Peripheral Neuropathy MONDO ID: MONDO:0029131 OMIM phenotype: #618124 (Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, PNRIID) Gene: MCM3AP (OMIM *603294; HGNC:6946), encoding GANP, chromosome 21q22.3 Category: Mendelian, autosomal recessive

Summary

MCM3AP-related peripheral neuropathy is an ultra-rare, autosomal-recessive, childhood-onset Charcot–Marie–Tooth (CMT) disorder caused by biallelic (compound heterozygous or homozygous) loss-of-function or hypomorphic variants in MCM3AP. This gene encodes GANP (Germinal-center–Associated Nuclear Protein), the Sac3-domain scaffold subunit of the human TREX-2 (transcription–export-2) complex that docks at the nuclear pore and hands newly transcribed messenger ribonucleoprotein particles (mRNPs) to the NXF1–NXT1 export receptor. The landmark disease-defining study identified biallelic MCM3AP variants in nine affected individuals from five unrelated families, presenting with severe childhood-onset primarily axonal (four families) or demyelinating (one family) CMT, with mild-to-moderate intellectual disability in seven of nine individuals (PMID: 28633435).

Mechanistically, pathogenic variants deplete GANP, impairing TREX-2-mediated mRNP remodeling and nuclear mRNA export. GANP uses a conserved "trigger loop" to release the DEAD-box helicase DDX39B/UAP56 and complete the mRNP remodeling cycle before export; loss of this function is proposed to drive length-dependent axonal degeneration of peripheral motor and sensory neurons, with a downstream branch involving R-loop formation and transcription-coupled genome instability. The mRNA-export defect alters gene expression in a manner dependent on transcript intron content, which may explain the selective vulnerability of long-axoned neurons.

The phenotype is a spectrum rather than a single presentation. Beyond core sensorimotor CMT with variable cognitive impairment, reported expansions include co-occurring multiple-sclerosis-like CNS demyelination, a motor-neuronopathy/anterior-horn presentation with widespread fasciculations, ptosis, and (in the earliest human report predating the neuropathy papers) a multisystem picture of immunodeficiency, genomic instability, skin changes, and myelodysplasia — reflecting GANP's additional roles in DNA repair, homologous recombination, and B-cell affinity maturation. A genotype–phenotype correlation exists: variants located outside the Sac3 domain produce more severe, earlier-onset disease with motor and cognitive impairment than variants within the Sac3 domain. There is currently no disease-modifying therapy; management is supportive and rehabilitative.

Section 1 — Disease Information

Overview. MCM3AP-related peripheral neuropathy is a Mendelian, recessively inherited, childhood-onset Charcot–Marie–Tooth (CMT) neuropathy, frequently accompanied by intellectual disability. It belongs to the broad group of inherited peripheral neuropathies but is distinguished by its causal gene (MCM3AP/GANP), its role in nuclear mRNA export, and its expanding multisystem spectrum.

Key identifiers.

Resource Identifier
MONDO MONDO:0029131
OMIM (phenotype) #618124
Gene MCM3AP (OMIM *603294; HGNC:6946); Ensembl ENSG00000160294
Cytogenetic location 21q22.3 (chr21:46,235,133–46,286,297, GRCh38)
Protein GANP / MCM3AP (UniProt O60318)
MeSH-related Charcot-Marie-Tooth Disease

Synonyms / alternative names. MCM3AP-related CMT; MCM3AP-associated peripheral neuropathy; recessive Charcot–Marie–Tooth neuropathy with intellectual disability; GANP-related neuropathy; "Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development" (PNRIID). GANP = Germinal-center–Associated Nuclear Protein; MCM3AP = Minichromosome Maintenance Complex Component 3 Associated Protein.

Information source. Information is derived from aggregated disease-level and individual patient reports in the published literature (case series and small cohorts), not from EHR-scale datasets. Cohorts to date include ~9 individuals in the founding study, a 28-individual retrospective series, and additional single-family reports.

Section 2 — Etiology

Disease causal factors. The disease is monogenic and genetic: biallelic pathogenic variants in MCM3AP. There is no environmental or infectious cause. Inheritance is autosomal recessive; affected individuals carry two damaging alleles (homozygous in consanguineous families, or compound heterozygous). GANP is essential — complete null of both alleles is presumed embryonic-lethal (the human disease results from hypomorphic combinations that retain residual function), consistent with animal data showing early requirement.

Genetic risk factors. The sole established genetic risk factor is possession of two pathogenic/hypomorphic MCM3AP alleles. Constraint data from gnomAD (see Section 4) show the gene tolerates heterozygous loss of function (pLI ≈ 0), so single-allele carriers are unaffected — fully in keeping with a recessive mechanism.

Environmental risk factors. None identified. Family history / consanguinity increases the a-priori risk of an affected child in the usual autosomal-recessive manner. Age and sex are not established risk modifiers.

Protective factors. No genetic or environmental protective factors have been described specifically for this disease.

Gene–environment interactions. None documented for MCM3AP-related neuropathy. The disease is essentially fully genetically determined given a biallelic pathogenic genotype, though variant-specific residual GANP function (allelic severity) is the dominant modifier of expression (see Section 4).

Section 3 — Phenotypes

Phenotypes are drawn primarily from the founding cohort (PMID: 28633435), the 28-individual retrospective series (PMID: 39228414), and single-family expansions.

Phenotype Type Onset Severity / Course Frequency Suggested HPO
Peripheral sensorimotor neuropathy (axonal or demyelinating CMT) Clinical sign Childhood Severe, progressive Core feature (essentially all) HP:0009830 (Peripheral neuropathy); HP:0007002 (Motor axonal neuropathy)
Distal muscle weakness / motor developmental delay Physical manifestation Childhood Variable–severe, progressive Common; delayed independent walking in null genotypes HP:0002460 (Distal muscle weakness); HP:0001270 (Motor delay)
Intellectual disability / cognitive impairment Behavioral / cognitive Childhood Mild–moderate; "with or without" 7/9 in founding cohort; 46.7% (Sac3) vs 100% (non-Sac3) HP:0001249 (Intellectual disability)
Areflexia / hyporeflexia Clinical sign Childhood Progressive Common HP:0001284 (Areflexia)
Distal sensory loss Symptom Childhood Progressive Common in classic sensorimotor form HP:0008936 (Sensory neuropathy)
Widespread fasciculations (motor-neuronopathy variant) Clinical sign Variable Novel, motor-predominant Rare (single report) HP:0002380 (Fasciculations)
Ptosis Physical manifestation Variable Mild Subset HP:0000508 (Ptosis)
Pes cavus / foot deformity Physical manifestation Childhood Progressive Common in CMT generally HP:0001761 (Pes cavus)
CNS demyelination (MS-like) Clinical sign Adult Inflammatory Rare (one family) HP:0007305 (CNS demyelination)
Immunodeficiency / myelodysplasia / skin changes Lab + clinical Variable Multisystem Rare (earliest human report) HP:0002721 (Immunodeficiency); HP:0002863 (Myelodysplasia)

Onset and severity generalities. Onset is typically childhood with a progressive course. Severity is variable and correlates with genotype: null / non-Sac3-domain variants trend toward earlier onset, delayed independent walking, greater motor and cognitive involvement, and higher risk of loss of ambulation.

Quality-of-life impact. No formal EQ-5D / SF-36 / PROMIS data exist for this ultra-rare disease. By analogy to severe childhood CMT, the combination of progressive distal weakness, sensory loss, foot deformity, and (frequently) intellectual disability substantially affects mobility, independence, education, and daily functioning; loss of ambulation is reported in more severe (null) genotypes.

Supporting quotes:

"The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals." — PMID: 28633435

"Neurological examination revealed generalized areflexia and widespread fasciculations without sensory abnormalities." — PMID: 41819534

Section 4 — Genetic / Molecular Information

Causal gene. MCM3AP (HGNC:6946; OMIM gene *603294), encoding GANP, located at chromosome 21q22.3 (chr21:46,235,133–46,286,297, GRCh38). The mouse ortholog Mcm3ap is on chromosome 10 (PMID: 27235683).

Protein architecture. GANP is a large, multidomain, bifunctional nucleoporin-associated protein containing: - an N-terminal HAT-like / FG (phenylalanine-glycine) region and histone-acetyltransferase (HAT) domain (PMID: 23652018); - MCM3-acetylating / DNA-replication-licensing activity; - a C-terminal Sac3 domain (the "MCM3AP domain"), homologous to Saccharomyces Sac3, which defines the TREX-2 mRNA-export scaffold (PMID: 27235683).

"GANP, encoded by human chromosome 21, as well as its mouse equivalent on chromosome 10, contains a region homologous to Saccharomyces Sac3 that was characterized as a component of the transcription/export 2 (TREX-2) complex and was predicted to be involved in RNA export and metabolism in mammalian cells." — PMID: 27235683

Pathogenic variants — types and classification. Reported variant classes span missense, nonsense, frameshift, splice-site, and large multi-exon deletions; genotypes are typically compound heterozygous or homozygous. Selected reported variants:

Variant Type Notes Source
c.1_5426del (loss of exons 1–25) Large deletion / likely null Paternal allele, index Chinese family PMID: 39228414
c.1858+3A>G Splice (deletes exon 5) Maternal allele, index Chinese family PMID: 39228414
c.5634-1G>T Splice-acceptor / NMD Novel splice variant PMID: 32319184
c.2633G>A (p.Arg878His) Missense Recurrent known variant PMID: 32319184
p.Ile954Thr Missense (Sac3 domain) Homozygous, CMT + MS family PMID: 32954258

Variants are classified pathogenic / likely pathogenic per ACMG/AMP criteria (null variants meeting PVS1; recurrent missense with functional and segregation support). Additional novel variants have been reported in Lebanese families (PMID: 29982295) and neuromuscular cohorts (PMID: 34602496).

Population allele frequency and constraint. gnomAD v2/v4 constraint metrics for MCM3AP (ENSG00000160294): pLI = 3.0e-28 (~0), observed/expected LoF (oe_lof) = 0.68 (126 observed vs 184.1 expected LoF; 90% CI/LOEUF 0.59–0.79), missense Z = −0.14 (no missense constraint), LoF Z = 3.63. These confirm that the gene tolerates heterozygous loss of function, consistent with the recessive mechanism — single carriers are unaffected, and disease requires biallelic hits.

Somatic vs germline. All disease-causing variants are germline. (Note: the MCM3AP-AS1 antisense lncRNA is separately implicated in various cancers, but this is unrelated to the neuropathy phenotype and involves somatic/expression dysregulation, not the coding neuropathy variants.)

Functional consequences. Predominantly loss of function / hypomorphic. Patient fibroblasts from one family showed severe depletion of GANP (PMID: 28633435). Functional work confirmed that different variants perturb GANP differently and that GANP loss alters gene expression depending on intron content (PMID: 32202298).

Modifier genes. No independent modifier genes are established; the principal modifier of severity is the specific allele combination and, notably, variant location relative to the Sac3 domain (see below).

Genotype–phenotype correlation. In the 28-individual retrospective series (PMID: 39228414):

"all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities)."

Feature Variants OUTSIDE Sac3 domain Variants WITHIN Sac3 domain
Early-onset symptoms 100% Lower
Motor developmental delay 100% 26.7%
Cognitive abnormalities 100% 46.7%

Epigenetic information / chromosomal abnormalities. No recurrent large-scale chromosomal abnormalities (aneuploidy, translocation) cause the disease, though multi-exon deletions occur. GANP itself participates in chromatin modification (its HAT domain modifies chromatin at rearranged immunoglobulin loci), but disease-specific epigenetic signatures are not established.

Section 5 — Environmental Information

MCM3AP-related peripheral neuropathy is a purely genetic Mendelian disorder. There are: - No environmental factors (toxins, radiation, pollution, occupational exposure) known to cause or trigger it. - No lifestyle factors (smoking, diet, exercise, alcohol) established as contributory. - No infectious agents implicated.

(Environmental toxins such as vincristine cause peripheral neuropathy through unrelated mechanisms; this is not relevant to the MCM3AP genetic etiology.)

Section 6 — Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic hypomorphic/LoF MCM3AP variants (missense, splice, frameshift, nonsense, multi-exon deletions) lead to reduced or dysfunctional GANP protein (severe GANP depletion demonstrated in patient fibroblasts). (Demonstrated.)
  2. GANP depletion results in loss of the Sac3-scaffold subunit of the nuclear-pore-docked TREX-2 complex (GANP–PCID2–DSS1–ENY2–centrin). (Demonstrated for GANP's TREX-2 role.)
  3. Loss of functional TREX-2 impairs handoff of mRNPs to the NXF1–NXT1 export receptor and impairs the conserved "trigger-loop"–mediated release of the DEAD-box helicase DDX39B/UAP56 that completes mRNP remodeling. (Demonstrated biochemically/structurally.)
  4. Impaired mRNP remodeling results in defective nuclear mRNA export — the proposed core pathogenic mechanism. (Demonstrated for mechanism; inferred as disease driver.)
  5. Defective export alters gene expression in a transcript-intron-content-dependent manner, leading to selective perturbation of a subset of neuronal transcripts. (Demonstrated in cell models.)
  6. Branch A (primary, neuronal): altered expression of critical transcripts in long-axoned peripheral neurons leads to length-dependent axonal degeneration → clinical CMT (motor + sensory). (Inferred.)
  7. Branch B (genome instability): retained/unexported mRNA leads to R-loop formation and transcription-coupled DNA damage → contributes to cellular dysfunction and, in some genotypes, multisystem features (immune, hematologic). (Demonstrated as a consequence of impaired export; contribution to neuropathy inferred.)
  8. Axonal degeneration results in distal weakness, sensory loss, areflexia, foot deformity; concurrent effects on CNS neurons result in intellectual disability in a genotype-dependent majority. (Clinical correlation.)
 MCM3AP biallelic variants
  │
  ▼
   GANP depletion / dysfunction  ── (also loses HAT / MCM3-acetylation / AID-shepherding roles)
  │
  ▼
   TREX-2 scaffold loss at nuclear pore
  │
  ▼
   Failure to release DDX39B/UAP56  →  impaired mRNP remodeling
  │
  ▼
   Defective nuclear mRNA export
┌──────────────┴───────────────┐
▼                              ▼
 Intron-content-dependent        R-loop formation /
 gene-expression changes         transcription-coupled
│                        DNA damage (genome instability)
▼                              ▼
 Length-dependent axonal          Multisystem features:
 degeneration (motor+sensory)     immunodeficiency, myelodysplasia,
│                          skin changes (subset)
▼
 CMT neuropathy ± intellectual disability

Detail by category

  • Molecular pathways. Nuclear mRNA export / TREX-2 pathway (GO:0006406 mRNA export from nucleus; GO:0016973 poly(A)+ mRNA export). NXF1–NXT1 receptor engagement; DDX39B/UAP56 ATPase cycle. GANP also intersects DNA-damage-induced NF-κB signaling and homologous-recombination DNA repair (via DNA-PKcs).
  • Cellular processes. Nucleocytoplasmic transport; mRNP assembly/remodeling; DNA double-strand-break repair pathway choice (HR vs NHEJ); chromatin modification (HAT domain); transcription-coupled genome maintenance; neuronal (axonal) maintenance.
  • Protein dysfunction. Predominantly loss of function through protein depletion (null/hypomorphic alleles) or domain-specific impairment (Sac3-domain missense). Variant-specific effects confirmed.
  • Immune-system involvement. GANP shepherds activation-induced cytidine deaminase (AID) to the nucleus and immunoglobulin variable loci, biasing DNA repair toward homologous recombination during somatic hypermutation and antibody affinity maturation — explaining immunodeficiency in the multisystem subset.
  • Tissue-damage mechanisms. R-loop-driven transcription-coupled DNA damage; genome instability. Length-dependent axonal degeneration in peripheral nerve.
  • Metabolic / metabolomic / lipidomic / proteomic changes. No disease-specific signatures established.
  • Molecular profiling / transcriptomics. RNA-seq of GANP/TREX-2-perturbed cells shows altered nucleocytoplasmic ratios of transcript subsets, with intron content and GC content influencing which mRNAs are affected (PMID: 32202298; related structural/RNA-seq work PMID: 40595470).

Key supporting quotes:

"Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients." — PMID: 28633435

"Here, we identify the conserved TREX-2 complex as the long-sought factor that facilitates DDX39B/Sub2 to complete the mRNP remodeling cycle." — PMID: 39862860

"Impaired mRNA export is closely related to DNA damage through R-loop formation." — PMID: 39769375

Suggested GO / CL terms. GO:0006406 (mRNA export from nucleus); GO:0016973 (poly(A)+ mRNA export from nucleus); GO:0000724 (double-strand break repair via homologous recombination); GO:0016573 (histone acetylation); GO:0031965 (nuclear membrane); GO:0044613 (nuclear pore central transport channel). Cell types: CL:0000101 (sensory neuron), CL:0000100 (motor neuron), CL:0002573 (Schwann cell), CL:0000540 (neuron).

Section 7 — Anatomical Structures Affected

Organ / system level. - Primary: peripheral nervous system (UBERON:0000010) — peripheral nerves (UBERON:0001021), especially long motor and sensory axons. - Secondary/associated: central nervous system (UBERON:0001017) — cerebral involvement underlying intellectual disability; CNS white matter in MS-like cases. Anterior horn / spinal cord (UBERON:0002240) in the motor-neuronopathy variant. Skeletal muscle (UBERON:0001134) — neurogenic changes and selective fatty infiltration on MRI. - Body systems: nervous (primary); in the multisystem subset also immune/hematopoietic and integumentary (skin).

Tissue / cell level. - Nervous tissue; peripheral motor and sensory neurons (axonal degeneration), Schwann cells / myelin in demyelinating cases, anterior horn (lower motor) neurons in the motor-neuronopathy variant. - Suggested CL terms: CL:0000100 (motor neuron), CL:0000101 (sensory neuron), CL:0002573 (Schwann cell), CL:0000236 (B cell — for AID-related immune features).

Subcellular level. - Nucleus and nuclear pore complex / nuclear envelope (where TREX-2/GANP operates) — GO:0005643 (nuclear pore), GO:0031965 (nuclear membrane), GO:0005634 (nucleus). Nucleocytoplasmic mRNA transport machinery.

Localization / lateralization. Peripheral neuropathy is bilateral and symmetric, length-dependent (distal-predominant, legs before arms) in classic CMT; the reported muscle-MRI pattern in the motor-neuronopathy variant is described as selective and non-length-dependent fatty infiltration.

Section 8 — Temporal Development

  • Onset. Typically childhood-onset; described as "severe childhood onset" in the founding cohort. Onset is insidious/chronic, not acute. Null / non-Sac3 genotypes present earliest (delayed independent walking, early motor developmental delay).
  • Progression. Progressive course. Motor developmental delay and, in severe genotypes, eventual loss of ambulation. Rate is variable and genotype-dependent (rapid/severe with null alleles; milder/slower with Sac3-domain missense). Electrophysiology in the motor-neuronopathy variant showed a "diffuse mixed acute-on-chronic denervation process."
  • Disease course pattern. Chronic, progressive, lifelong. The rare co-occurring MS-like CNS demyelination may add a relapsing inflammatory component.
  • Remission / critical periods. No spontaneous remission. Childhood is the critical window of neurodevelopmental and motor-skill acquisition; any future disease-modifying intervention would ideally act early.

"Electroneuromyography demonstrated diffuse mixed acute-on-chronic denervation process. Whole-body muscle MRI showed a selective non-length-dependent pattern of fatty infiltration." — PMID: 41819534

Section 9 — Inheritance and Population

Epidemiology. Ultra-rare. No formal prevalence or incidence estimates exist (fewer than ~40–60 individuals reported worldwide across all cohorts). Not listed with a specific population-scale prevalence figure in Orphanet.

Inheritance and genetics. - Inheritance pattern: Autosomal recessive (compound heterozygous or homozygous). Confirmed by segregation and by gnomAD constraint showing heterozygous-LoF tolerance. - Penetrance: Appears high/complete for the neuropathy phenotype in biallelic individuals, though expressivity is highly variable (severity and cognitive involvement genotype-dependent). - Expressivity: Variable — from milder Sac3-domain phenotypes to severe early-onset non-Sac3 phenotypes, and multisystem presentations. - Genetic anticipation: Not applicable (not a repeat-expansion disorder). - Germline mosaicism: Not reported. - Founder effects: No established founder mutation; recurrent variants (e.g., p.Arg878His) noted across reports. - Consanguinity: Plays the expected role in homozygous cases (e.g., consanguineous families with homozygous Sac3-domain missense). - Carrier frequency: Not precisely established; gnomAD LoF observed count (126) implies rare heterozygous carriers in the general population; biallelic disease is correspondingly very rare.

Population demographics. Reported across multiple ethnicities/geographies (European, Chinese, Lebanese, others) — no single population enrichment. Sex ratio is not reported to be skewed (autosomal recessive; expected ~1:1 male:female). Age distribution centers on pediatric onset with lifelong course.

Section 10 — Diagnostics

Clinical / electrophysiology. - Nerve conduction studies / EMG: define CMT subtype — reduced amplitudes (axonal) or slowed conduction velocities (demyelinating). In the motor-neuronopathy variant, ENMG showed a "diffuse mixed acute-on-chronic denervation process." - Whole-body / muscle MRI: the motor-neuronopathy case showed a "selective non-length-dependent pattern of fatty infiltration," a potentially distinguishing imaging clue. - Neurological exam: distal weakness, sensory loss, areflexia/hyporeflexia, pes cavus; in the motor variant, generalized areflexia with widespread fasciculations and no sensory abnormality. - Nerve biopsy: not routinely required; would show axonal loss (axonal form) or demyelination/onion-bulbs (demyelinating form) — nonspecific.

Genetic testing (definitive). - Recommended approach: since phenotype overlaps many CMT genes, next-generation sequencing (WES/WGS or a large inherited-neuropathy gene panel including MCM3AP) is the diagnostic route. Single-gene testing is reasonable only when phenotype and family history are highly suggestive. - WES/WGS: high utility — the disease gene was discovered by exome sequencing across multiple centers via gene-matching. WGS/CNV analysis is important because large multi-exon deletions and splice variants occur and may be missed by panel/coverage gaps. - Chromosomal microarray / CNV analysis: useful to detect multi-exon deletions (e.g., c.1_5426del). - Confirmatory functional testing: GANP protein quantification (Western blot) in patient fibroblasts can support pathogenicity (severe depletion demonstrated). - Not applicable: karyotyping, FISH, mtDNA testing, and repeat-expansion testing are not indicated.

Omics-based diagnostics. RNA-seq can demonstrate splice consequences (e.g., NMD-mediated transcript loss) and intron-content-dependent expression changes, useful for variant interpretation. No proteomic/metabolomic clinical assay exists.

Clinical criteria / differential diagnosis. No formal consensus diagnostic criteria beyond CMT classification plus molecular confirmation. Differential diagnosis includes other recessive childhood-onset CMT genes (e.g., SH3TC2, GDAP1, IGHMBP2), CMT-with-intellectual-disability syndromes, hereditary motor neuronopathies / SMA (for the motor-neuronopathy variant), and — in the MS-overlap family — acquired inflammatory CNS demyelination. Molecular genetic testing distinguishes MCM3AP disease.

Screening. For at-risk families: cascade / carrier testing of relatives and prenatal / preimplantation genetic testing once the familial variants are known. No population newborn screening exists.

Section 11 — Outcome / Prognosis

  • Survival / mortality. Not a directly life-limiting neuropathy in most reports; no specific survival or mortality statistics are available. The multisystem/immunodeficiency-myelodysplasia subset could carry additional risk, but data are limited to single reports.
  • Morbidity / function. Substantial. Progressive distal weakness and sensory loss cause mobility impairment; severe (null) genotypes may lose ambulation. Intellectual disability (mild–moderate) adds educational and functional burden in the majority. Formal disability/QoL measures have not been applied.
  • Complications. Foot deformities, contractures, falls, and complications of immobility; in demyelinating-CNS and immunodeficiency subsets, additional neurological or infectious complications.
  • Recovery potential. No spontaneous recovery; the process is progressive and there is no curative therapy.
  • Prognostic factors. The strongest predictor is genotype: null / non-Sac3-domain variants predict earlier onset, delayed walking, greater motor and cognitive impairment, and higher risk of loss of ambulation; Sac3-domain missense predicts milder disease. No molecular prognostic biomarker beyond genotype is established.

"affected individuals with null mutations presented with delayed independent walking" — PMID: 32319184

Section 12 — Treatment

There is currently no disease-modifying or curative therapy. Management is supportive, symptomatic, and rehabilitative, mirroring general CMT care.

  • Pharmacotherapy. No targeted drug. Symptomatic agents may include neuropathic-pain medications (e.g., gabapentinoids, duloxetine) where painful sensory symptoms occur (NCIT clinical-intervention category: analgesic / neuropathic-pain pharmacotherapy). No pharmacogenomic guidance specific to MCM3AP.
  • Advanced therapeutics. None approved. Gene therapy, RNA-based therapies, cell therapy, and targeted molecular therapies are conceptually plausible future directions (see follow-up) but not available. Because the mechanism is loss of function, gene-replacement / augmentation strategies are theoretically rational.
  • Surgical / interventional. Orthopedic correction of foot deformities (e.g., tendon transfer, osteotomy) and management of contractures as needed (NCIT: orthopedic surgical procedure).
  • Supportive / rehabilitative. Physical therapy, occupational therapy (NCIT:C15533 Rehabilitation Therapy; NCIT:C15629 Physical Therapy; NCIT:C15236 Occupational Therapy), orthoses (ankle-foot orthoses), assistive/mobility devices, fall prevention; speech/educational support for intellectual disability; multidisciplinary neuromuscular care.
  • Experimental. No disease-specific registered clinical trials identified.
  • Treatment strategy. Individualized, multidisciplinary, supportive care coordinated by neuromuscular specialists, with genetic counseling for the family.

Section 13 — Prevention

  • Primary prevention. Because the disease is monogenic and recessive, "prevention" operates at the reproductive-genetics level rather than through lifestyle/environmental modification. Options include genetic counseling, carrier testing of relatives, and, for known-carrier couples, preimplantation genetic testing (PGT) or prenatal diagnosis.
  • Secondary prevention. Early molecular diagnosis enables early rehabilitative intervention, orthotic management, educational support, and surveillance for complications.
  • Tertiary prevention. Prevent complications of progressive weakness (contractures, falls, skin breakdown) via PT/OT, orthoses, and monitoring; in the multisystem subset, monitor immune/hematologic status.
  • Counseling. Genetic counseling is central: recurrence risk is 25% for future children of two carrier parents; carrier and cascade testing offered to at-risk relatives.
  • Immunization / public-health / environmental interventions. Not applicable (no infectious or environmental etiology). Standard immunizations advisable generally, particularly if immunodeficiency features are present.

Section 14 — Other Species / Natural Disease

  • Taxonomy / orthologs. MCM3AP/GANP is evolutionarily conserved. Human MCM3AP (chr21); mouse Mcm3ap (chromosome 10, NCBI Gene ID 54387). Functional orthologs of the Sac3/TREX-2 scaffold exist in Drosophila ("Xmas-2" / protein x-mas-2), budding yeast (Sac3, in the yeast TREX-2 complex), and other eukaryotes.
  • Natural disease in other species. No naturally occurring companion-animal or wildlife disease attributable to MCM3AP is documented in OMIA; the disease is currently described only in humans.
  • Comparative biology. The mechanism (TREX-2-mediated mRNA export and mRNP remodeling; DDX39B/Sub2 release via a conserved trigger loop) is strikingly conserved from yeast to humans, making invertebrate and yeast systems informative for mechanism even though they do not model the clinical neuropathy.
  • Transmission. Not applicable (non-infectious, non-zoonotic).

Section 15 — Model Organisms

  • Drosophila melanogaster. GANP (via its ortholog) suppresses TDP-43-mediated motor-neuron degeneration in flies — the most direct disease-relevant model linking GANP to motor-neuron protection (cited in PMID: 28633435). Insect studies (fly/mosquito/beetle) also confirm MCM3AP's essential developmental role (knockdown lethality), supporting essentiality.
  • Mouse (Mcm3ap). Genetically modified mice exist, including conditional ganp-knockout and ganp-transgenic lines used primarily to study immune/germinal-center biology and tumorigenesis; GANP expression is "highly associated with tumorigenesis in mice and humans," demonstrated "using genetically modified mice" (PMID: 39769375; immune models PMID: 23652018, PMID: 27235683). A dedicated mouse model recapitulating the peripheral neuropathy phenotype is not yet established — a key gap.
  • Chicken DT40 B-cell line. Used to dissect GANP's role in DNA-repair pathway choice (HR vs NHEJ) during AID-dependent Ig diversification (PMID: 24808370).
  • Yeast (Saccharomyces cerevisiae). Sac3/TREX-2 provides the mechanistic template for the human complex; ortholog Thp3–Csn12 informs the mRNP surveillance/decay branch.
  • Patient-derived cells. Fibroblasts (GANP depletion; DNA-repair assays) and cell-line RNA-seq models are the principal human-relevant systems used to date; iPSC-derived neurons/organoids would be a logical next model.

Phenotype recapitulation / limitations. Existing genetic models capture GANP's molecular roles (mRNA export, DNA repair, immune maturation, tumorigenesis) well, but no current model fully recapitulates the human peripheral-neuropathy-with-intellectual-disability phenotype. The fly TDP-43 model captures motor-neuron protection but not the full clinical spectrum.

Mechanistic Model / Interpretation (synthesis)

MCM3AP-related neuropathy is best understood as a "mRNP-export-opathy" of long neurons. GANP sits at the nuclear pore as the Sac3 scaffold of TREX-2, orchestrating the final steps of mRNP maturation: it engages the NXF1–NXT1 export receptor and, via a conserved trigger loop, evicts DDX39B/UAP56 to license export. When biallelic variants deplete or cripple GANP, this handoff fails. The consequence is not global translational collapse but a selective, intron-content-dependent distortion of the transcriptome — which plausibly explains why the longest, most transcript-demanding cells (peripheral motor/sensory axons and, less severely, CNS neurons) are preferentially affected, yielding length-dependent axonal degeneration and intellectual disability. A parallel branch — R-loop-driven, transcription-coupled genome instability — provides a unifying explanation for the multisystem outliers (immunodeficiency, myelodysplasia, skin changes) reported in the earliest human case and for GANP's established roles in AID shepherding and HR-biased DNA repair.

The Sac3-domain genotype–phenotype axis is the report's most clinically actionable synthesis: variants outside the Sac3 domain (often more disruptive to the protein overall / closer to null) uniformly cause early-onset motor-and-cognitive disease, whereas Sac3-domain missense variants (which may retain partial scaffold function) cause milder disease. This gradient, together with gnomAD constraint showing heterozygous-LoF tolerance, cements a loss-of-function, dosage-sensitive recessive model in which residual GANP activity sets severity.

Evidence Base

PMID Title (abbrev.) Contribution
28633435 MCM3AP in recessive CMT and mild intellectual disability Landmark: establishes MCM3AP/GANP as the disease gene; 9 individuals/5 families; axonal vs demyelinating; ID in 7/9; GANP depletion; mRNA-export mechanism
28969388 Biallelic MCM3AP mutations cause CMT with variable presentation Second 2017 cohort confirming variable clinical spectrum
39228414 Biallelic MCM3AP mutations (28 individuals) Genotype–phenotype: Sac3 vs non-Sac3 severity; novel c.1_5426del and c.1858+3A>G
32954258 Recessive CMT and MS with MCM3AP variant Phenotype expansion: CMT + CNS demyelination; p.Ile954Thr; MCM3-acetylation role
41819534 Motor neuronopathy with fasciculations in MCM3AP disorder Novel anterior-horn/motor-neuronopathy phenotype; ENMG and muscle-MRI findings
32319184 Novel MCM3AP variants c.5634-1G>T and p.Arg878His; null genotypes → delayed independent walking
32202298 Distinct effects on GANP; intron-content-dependent expression Variant-specific GANP effects; intron-content-dependent gene-expression mechanism
26615982 De novo MCM3AP + POMP; immunodeficiency/genomic instability Earliest human report; GANP DNA-repair/HR/NF-κB/AID roles; multisystem phenotype
27235683 GANP in RNA metabolism for B-cell maturation Gene location, mouse ortholog, Sac3/TREX-2 domain
23652018 GANP HAT domain modulates AID recruitment HAT domain / chromatin-modifying function
20507984 GANP-mediated recruitment of AID AID shepherding — second major GANP function
24808370 GANP regulates DNA repair pathway choice via DNA-PKcs HR-vs-NHEJ pathway choice; DT40 model
39769375 Tumorigenesis from aberrant GANP in TREX-2 R-loop/genome-instability branch; mouse models
39862860 Structures and mRNP remodeling of TREX-2 TREX-2 completes DDX39B/Sub2 mRNP remodeling cycle
40595470 DDX39B regulation by TREX-2 Trigger-loop mechanism; GC-content-dependent mRNA effects
39384042 NS1-BP/NXF1 mRNA export Confirms GANP–NXF1 partnership in export

Evidence-type distribution: human clinical (case series/cohorts) for phenotype, inheritance, and genotype–phenotype; human patient-derived cells for GANP depletion and DNA-repair defects; in vitro/structural biochemistry for the TREX-2/DDX39B mechanism; model-organism (fly, mouse, DT40, yeast) for GANP's molecular and immune functions; computational (gnomAD) for constraint.

Limitations and Knowledge Gaps

  1. Ultra-rare disease, small n. Total reported individuals number only in the low tens; prevalence, incidence, survival, QoL, and natural-history data are essentially absent.
  2. Mechanism partly inferred. Defective nuclear mRNA export is demonstrated at the molecular level and strongly implicated, but the direct causal link from export defect to peripheral axonal degeneration in humans remains inferred, not proven in a neuronal disease model.
  3. No neuropathy-specific animal model. Existing mouse models address immunity and tumorigenesis, not the peripheral-neuropathy phenotype; the fly TDP-43 model is partial.
  4. Genotype–phenotype correlation is retrospective and based on limited cohorts; the Sac3-domain rule needs prospective validation and functional dissection.
  5. Selective neuronal vulnerability unexplained mechanistically — why long axons and cognition are targeted while most tissues are spared is not fully resolved (the intron-content hypothesis is promising but incomplete).
  6. Multisystem spectrum boundaries unclear — the relationship between the neuropathy-dominant presentations and the immunodeficiency/myelodysplasia presentations (allelic series? modifier genes?) is not established.
  7. No therapeutics and no biomarkers of progression beyond genotype.

Proposed Follow-up Experiments / Actions

  1. Build a neuronal disease model. Generate patient-derived iPSC motor/sensory neurons and cerebral organoids, plus a conditional neuron-specific Mcm3ap hypomorph mouse, to test whether GANP loss produces axonal degeneration and to define the affected transcript set in neurons.
  2. Define the vulnerable transcriptome. Perform nucleocytoplasmic fractionation RNA-seq in patient neurons to map which intron-/GC-rich transcripts are export-impaired, linking specific mis-exported mRNAs to axonal maintenance.
  3. Functionally validate the Sac3 rule. Systematically assay GANP protein level, TREX-2 assembly, DDX39B release, and export activity for Sac3 vs non-Sac3 variants to convert the clinical correlation into a mechanistic severity scale usable for variant classification.
  4. Test the R-loop/genome-instability branch in neurons. Quantify R-loops and DNA damage in patient neurons; determine whether this branch contributes to neurodegeneration or is confined to the immune/hematologic phenotype.
  5. Establish a natural-history registry. Aggregate cases internationally (via GeneMatcher/consortia) to obtain prevalence, progression rates, ambulation outcomes, cognitive trajectories, and validated QoL measures.
  6. Explore gene-augmentation feasibility. Given the loss-of-function mechanism and heterozygous-LoF tolerance, evaluate AAV- or mRNA-based GANP restoration in cellular/animal models as a proof-of-concept therapeutic direction.
  7. Standardize diagnostics. Ensure inherited-neuropathy panels/WGS pipelines capture large multi-exon deletions and splice variants in MCM3AP, and incorporate GANP Western blot / RNA-seq as functional confirmation for VUS resolution.

Report compiled from 10 confirmed findings and 33 reviewed papers over 5 investigation iterations. Evidence types span human clinical cohorts, patient-derived cells, structural/in-vitro biochemistry, model organisms, and computational constraint analysis. Claims are attributed to primary literature by PMID with verbatim supporting quotes where provided.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 11
Quoted claims found in source 9
Quoted claims not found in source 2
References weighed for topical relevance 18
On topic 6
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:23652018 (abstract only): "using genetically modified mice"
  • Text part not found as substring: 'using genetically modified mice' (note: only abstract available for PMID:23652018, full text may contain this excerpt)
  • PMID:27235683 (abstract only): "using genetically modified mice"
  • Text part not found as substring: 'using genetically modified mice' (note: only abstract available for PMID:27235683, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 36
Resolved 34
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 22
Terms named correctly 16
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0029131 (2 mentions) - the report calls it "MONDO"; MONDO calls it peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
  • HP:0008936 (1 mention) - the report calls it "Sensory neuropathy"; HP calls it Axial hypotonia
  • CL:0000236 (1 mention) - the report calls it "B cell — for AID-related immune features"; CL calls it B cell

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0016573 (obsolete histone acetylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0016573 (1 mention) - the report calls it "histone acetylation"; GO calls it obsolete histone acetylation
  • UBERON:0000010 (1 mention) - the report calls it "Primary: peripheral nervous system"; UBERON calls it peripheral nervous system**
  • UBERON:0001017 (1 mention) - the report calls it "Secondary/associated: central nervous system"; UBERON calls it central nervous system**