Autosomal dominant aplasia and myelodysplasia (bone marrow failure syndrome 1, BMFS1; OMIM 614675) is an inherited bone marrow failure and myelodysplasia predisposition syndrome caused by heterozygous germline variants in SRP72, the 72 kDa subunit of the signal recognition particle. Reported families present with marrow hypocellularity, pancytopenia and adult- or childhood-onset myelodysplasia; congenital sensorineural deafness was present in the family in which the gene was first identified and is recorded alongside the haematologic phenotype in expert classifications of the inherited bone marrow failure syndromes. Its mechanistic interest is that it places a defect in *co-translational protein targeting* upstream of marrow failure. The signal recognition particle is a ribonucleoprotein of six proteins assembled on 7SL RNA that binds the signal sequence of a nascent secretory or membrane protein as it emerges from the ribosome and routes the ribosome-nascent-chain complex to the endoplasmic reticulum. That is a housekeeping function required by every cell, so it is a different kind of lesion from the five mechanistic axes already represented among the inherited aplastic anaemias in this knowledge base - DNA interstrand crosslink repair (Fanconi anaemia), telomere maintenance (dyskeratosis congenita), ribosome biogenesis and assembly (Diamond-Blackfan anaemia, Shwachman-Diamond syndrome), thrombopoietin receptor signalling (congenital amegakaryocytic thrombocytopenia), and inflammatory suppression of the stem compartment. SRP72 is a sixth axis rather than a variant of any of them, which is why it is curated as its own entry rather than folded into the parent. How a ubiquitous translocation defect produces a tissue-restricted haematopoietic phenotype is unresolved, and the literature says so directly. That gap is recorded here as a `KNOWLEDGE_GAP` discussion rather than papered over with an inferred chain, and the pathophysiology nodes below are deliberately few: they carry only what the references available to this entry actually support.
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name: Autosomal Dominant Aplasia and Myelodysplasia
creation_date: "2026-09-03T22:45:00Z"
category: Mendelian
disease_term:
preferred_term: autosomal dominant aplasia and myelodysplasia
term:
id: MONDO:0013851
label: autosomal dominant aplasia and myelodysplasia
description: >
Autosomal dominant aplasia and myelodysplasia (bone marrow failure syndrome 1,
BMFS1; OMIM 614675) is an inherited bone marrow failure and myelodysplasia
predisposition syndrome caused by heterozygous germline variants in SRP72, the
72 kDa subunit of the signal recognition particle. Reported families present
with marrow hypocellularity, pancytopenia and adult- or childhood-onset
myelodysplasia; congenital sensorineural deafness was present in the family in
which the gene was first identified and is recorded alongside the haematologic
phenotype in expert classifications of the inherited bone marrow failure
syndromes.
Its mechanistic interest is that it places a defect in *co-translational
protein targeting* upstream of marrow failure. The signal recognition particle
is a ribonucleoprotein of six proteins assembled on 7SL RNA that binds the
signal sequence of a nascent secretory or membrane protein as it emerges from
the ribosome and routes the ribosome-nascent-chain complex to the endoplasmic
reticulum. That is a housekeeping function required by every cell, so it is a
different kind of lesion from the five mechanistic axes already represented
among the inherited aplastic anaemias in this knowledge base - DNA interstrand
crosslink repair (Fanconi anaemia), telomere maintenance (dyskeratosis
congenita), ribosome biogenesis and assembly (Diamond-Blackfan anaemia,
Shwachman-Diamond syndrome), thrombopoietin receptor signalling (congenital
amegakaryocytic thrombocytopenia), and inflammatory suppression of the stem
compartment. SRP72 is a sixth axis rather than a variant of any of them,
which is why it is curated as its own entry rather than folded into the
parent.
How a ubiquitous translocation defect produces a tissue-restricted
haematopoietic phenotype is unresolved, and the literature says so directly.
That gap is recorded here as a `KNOWLEDGE_GAP` discussion rather than papered
over with an inferred chain, and the pathophysiology nodes below are
deliberately few: they carry only what the references available to this entry
actually support.
synonyms:
- BMFS1
- bone marrow failure syndrome 1
- bone marrow failure syndrome type 1
- SRP72 deficiency
- autosomal dominant aplastic anemia and myelodysplasia
- autosomal dominant aplastic anaemia and myelodysplasia
parents:
- Inherited aplastic anemia
- Bone marrow failure syndrome
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK571103/
title: "Monosomy 7 Predisposition Syndromes Overview - GeneReviews® - NCBI Bookshelf"
tags:
- GeneReviews
- reference: PMID:35748970
title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
- reference: PMID:37226705
title: "Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants."
- reference: PMID:22541560
title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
- reference: PMID:31254415
title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
- reference: PMID:40922878
title: "A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report."
- reference: PMID:41472573
title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
classifications:
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The IUIS classification table places SRP72 deficiency among the bone
marrow failure syndromes, a haematologic disorder and so Harrison's
haematology/oncology Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "BMFS1 (SRP72-deficiency) SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The row assigns the disease a single causal gene with a Mendelian mode
of inheritance and its own OMIM gene entry, which is what places it in
Harrison's genetics Part alongside the haematology assignment above -
the disease is approached diagnostically through germline sequencing of
that gene, not only as a marrow-failure phenotype.
iuis_category:
classification_value: bone marrow failure
notes: >-
IUIS 2022 phenotypic classification of inborn errors of immunity (Tangye et
al., PMID:35748970), Table 9 "Bone marrow failure", the row entered as "BMFS1
(SRP72-deficiency)". One row, one gene, and the row's own associated-features
cell states the phenotype this entry curates. The two harrisons_chapter
assignments above were already drawn from this same table row; this slot
records the nosology placement itself, which is what the Bone Marrow Failure
IEIs grouping reads. Note the table's OMIM number, 602122, is the SRP72 gene
entry rather than the phenotype entry 614675 that this disease is usually
cited under; the gene and the row label are what identify it.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "BMFS1 (SRP72-deficiency) SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The complete Table 9 row for this disease, naming it as bone marrow failure
syndrome 1, giving SRP72 as the gene and autosomal dominant as the mode of
inheritance, and describing bone marrow failure with congenital nerve
deafness. Graded OTHER because the cited source is an expert-committee
nosology, not a primary study.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Reported SRP72 variants are germline and heterozygous, and the IUIS
classification records the mode of inheritance as autosomal dominant. The
penetrance of the allele is not established - see the `srp72-penetrance`
discussion - so no penetrance value is set here.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The classification row records SRP72 with mode of inheritance AD
(autosomal dominant) against the gene's OMIM entry 602122.
genetic:
- name: SRP72
gene_term:
preferred_term: SRP72
term:
id: hgnc:11303
label: SRP72
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: >-
Heterozygous germline SRP72 variants are the established cause of bone
marrow failure syndrome 1. SRP72 encodes the 72 kDa subunit of the signal
recognition particle, one of the six proteins assembled on 7SL RNA.
evidence:
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a heterozygous mutation in SRP72, a component of the signal recognition particle (SRP) that is responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum."
explanation: >-
The gene-discovery report: exome sequencing in a family with autosomal
dominant AA/MDS identified a heterozygous SRP72 mutation, and states what
the gene product does.
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A subsequent screen revealed another autosomal-dominant family with an inherited heterozygous SRP72 mutation."
explanation: >-
A second independent family, which is what lifts the association above a
single-family observation.
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
Names SRP72 as the gene of BMFS1, with autosomal dominant inheritance and
a bone marrow failure phenotype.
- reference: PMID:37226705
reference_title: "Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "In eukaryotes, the SRP complex consists of six proteins arranged on a long, non-coding 7SL RNA, which help route the nascent polypeptides to the Golgi apparatus for further modification and shipping to specific subcellular compartments."
explanation: >-
Establishes what the gene product does: SRP72 is one of the six proteins
of the 7SL-RNA-based SRP complex that routes nascent polypeptides.
notes: >-
The specific alleles reported in the literature (including the founding
frameshift and missense variants) are not curated here because the primary
reports could not be fetched in this environment - see the entry-level
`notes`.
pathophysiology:
- name: SRP72 Deficiency
biological_scale: MOLECULAR
description: >-
A heterozygous germline SRP72 variant leaves the signal recognition particle
without normal SRP72 function. The IUIS classification names the entity
"SRP72-deficiency", which is the name used for this node.
The node is deliberately NOT named haploinsufficiency. "Deficiency" in a
classification table says a functional deficit exists; it does not say the
deficit is a halved dose of an otherwise normal subunit, and the primary
data argue against that reading: transfected mutant SRP72 mislocalizes
within the cell, and one of the two variants fails to associate normally
with the particle's essential 7SL RNA. Both point at a defect in
incorporating SRP72 into an assembled particle rather than at reduced gene
dosage, and a variant that misassembles could act on the particle rather
than merely be absent from it. The `Srp72+/-` mouse is the complementary
argument: halving the dose in mice produces no haematological disorder (see
`animal_models`). Which lesion operates is still open - see the
`srp72-molecular-lesion` discussion - so `functional_impact_category` is
left unset on the `genetic` block, because every value it could take would
assert a distinction the evidence does not yet settle.
genes:
- preferred_term: SRP72
term:
id: hgnc:11303
label: SRP72
downstream:
- target: Impaired SRP-Dependent Cotranslational Protein Targeting
description: >-
Loss of normal SRP72 function in the particle is the proximal cause of
reduced particle-level function, on either candidate lesion.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "BMFS1 (SRP72-deficiency) SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The expert classification names the disease entity "SRP72-deficiency".
That supports a functional deficiency of the subunit, which is what this
node claims; it does not distinguish reduced dosage from a misassembling
mutant subunit.
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "Transfection of these sequences into mammalian cells suggested that these proteins localize incorrectly within the cell."
explanation: >-
Direct cell-based evidence that the disease-associated SRP72 proteins are
functionally abnormal, not merely reduced in amount.
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants."
explanation: >-
Shows the deficiency is at the level of assembly onto 7SL RNA for one
variant, which is the observation that argues against simple
haploinsufficiency.
- name: Impaired SRP-Dependent Cotranslational Protein Targeting
biological_scale: MOLECULAR
description: >-
The signal recognition particle binds the signal sequence of a nascent
secretory or membrane protein and delivers the ribosome-nascent-chain
complex to the endoplasmic reticulum membrane. The gene-discovery report
names this as the function SRP72 serves, and shows the disease-associated
variants failing at it - mislocalizing in transfected cells, and in one case
not associating properly with 7SL RNA. What is still not measured in patient
cells is the rate of co-translational targeting itself, so the node states
the functional consequence the assembly defect implies rather than a
directly quantified one.
biological_processes:
- preferred_term: SRP-dependent cotranslational protein targeting to membrane
modifier: DECREASED
term:
id: GO:0006614
label: SRP-dependent cotranslational protein targeting to membrane
downstream:
- target: Impaired Haematopoietic Output
description: >-
The step from a ubiquitous targeting defect to a blood-restricted
phenotype is the unexplained link in this disease; see the
`srp72-tissue-restriction` discussion.
- target: Congenital sensorineural hearing impairment
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The one manifestation of SRP72 disease outside the blood, and the reason
the `srp72-tissue-restriction` discussion is framed as it is: a
ubiquitously required targeting pathway produces a phenotype that is
almost — but not entirely — haematopoietic. Attached here rather than to
the haematopoietic node because the hearing loss is congenital and is not
a consequence of marrow failure. No source traces a route from impaired
cotranslational targeting to cochlear development, so the intermediates
are recorded as unknown rather than guessed at.
evidence:
- reference: PMID:37226705
reference_title: "Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "For proteins directed to the endoplasmic reticulum, this process occurs co-translationally, which is mediated by the SRP complex."
explanation: >-
Establishes the function this node reports as impaired. Graded INDIRECT
because the quoted statement is about the SRP complex in general; it does
not itself measure targeting in SRP72-deficient cells.
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "These results suggest that inherited mutations in a component of the SRP have a role in the pathophysiology of AA/MDS, identifying a third pathway for developing these disorders alongside transcription factor and telomerase mutations."
explanation: >-
The primary report's own conclusion that an SRP-component defect is a
distinct pathophysiological route to AA/MDS, and the basis for curating
SRP72 as a separate mechanistic axis from the telomere and
transcription-factor axes on the parent entry. Graded INDIRECT: the
sentence asserts a role in AA/MDS pathophysiology, not that
co-translational targeting is itself measurably impaired.
- name: Impaired Haematopoietic Output
biological_scale: CELLULAR
description: >-
SRP72 is one of two SRP components linked to disordered granulocyte
production. The cited review reports that association without resolving
which haematopoietic compartments are affected or by what route, so this
node is stated at the level the source supports.
cell_types:
- preferred_term: hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
downstream:
- target: Bone marrow hypocellularity
description: >-
Reduced haematopoietic output is the cellular correlate of the
hypocellular marrow. The target is the HP-bound `phenotypes` entry: the
tissue-level finding is that phenotype, so it is not restated as a
separate pathophysiology node.
evidence:
- reference: PMID:37226705
reference_title: "Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "Two other components of the SRP complex, SRP72 and SRP19, are associated with dysgranulopoiesis."
explanation: >-
Links SRP72 specifically to a disorder of haematopoietic cell production.
notes: >-
Deliberately not conformed to the `stem_cell_exhaustion` module. That module
scopes itself in its own description to the age-associated decline of
tissue stem cells; asserting conformance from a germline targeting defect
would import an ageing mechanism that no source here supports. Also
deliberately not conformed to `myelosuppression`, whose description scopes
it to treatment toxicity.
phenotypes:
- category: Hematologic
name: Bone marrow hypocellularity
phenotype_term:
preferred_term: Bone marrow hypocellularity
term:
id: HP:0005528
label: Bone marrow hypocellularity
description: >-
A hypocellular marrow is the defining haematologic lesion of the syndrome,
and is the tissue-level node the causal chain terminates in before the
peripheral and clonal consequences below.
sequelae:
- target: Pancytopenia
description: Failure of marrow output presenting as peripheral cytopenias.
- target: Myelodysplasia
description: >-
The same marrow is the substrate for dysplastic and, in reported
families, clonally evolving haematopoiesis.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
The classification records bone marrow failure as the haematologic
phenotype associated with SRP72.
- category: Hematologic
name: Pancytopenia
phenotype_term:
preferred_term: Pancytopenia
term:
id: HP:0001876
label: Pancytopenia
description: >-
Peripheral pancytopenia is recorded as a haematologic feature of SRP72
bone marrow failure syndrome 1 in the GeneReviews survey of monosomy 7
predisposition syndromes.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK571103/
reference_title: "Monosomy 7 Predisposition Syndromes Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone marrow failure syndrome 1 (OMIM...Pancytopenia, myelodysplasia"
explanation: >-
Quotes the disorder cell and the haematologic-features cell of the
GeneReviews table row for SRP72, which records pancytopenia and
myelodysplasia as the haematologic phenotype of bone marrow failure
syndrome 1.
- category: Hematologic
name: Myelodysplasia
phenotype_term:
preferred_term: Myelodysplasia
term:
id: HP:0002863
label: Myelodysplasia
description: >-
Myelodysplasia is named in the disease concept itself and is recorded as a
haematologic feature in GeneReviews, which lists SRP72 among the genes
predisposing to monosomy 7 and myeloid neoplasia.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK571103/
reference_title: "Monosomy 7 Predisposition Syndromes Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone marrow failure syndrome 1 (OMIM...Pancytopenia, myelodysplasia"
explanation: >-
The same GeneReviews table row records myelodysplasia as a haematologic
feature of SRP72-related bone marrow failure syndrome 1.
- category: Neurological
name: Congenital sensorineural hearing impairment
phenotype_term:
preferred_term: Congenital sensorineural hearing impairment
term:
id: HP:0008527
label: Congenital sensorineural hearing impairment
description: >-
Congenital nerve deafness is recorded alongside the haematologic phenotype
in the IUIS classification. It is not a constant feature: a reported patient
with a pathogenic SRP72 frameshift had normal hearing tests, so the
deafness does not track the marrow phenotype allele for allele. No
frequency band is set here for the reason given in the entry-level `notes`.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "SRP72 AD 602122 NA NA Bone marrow failure and congenital nerve deafness"
explanation: >-
Records congenital nerve deafness as the non-haematologic feature
associated with SRP72 deficiency.
- reference: PMID:40922878
reference_title: "A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Some patients with SRP72 gene mutations have hearing loss, but our patient had normal results in the hearing test."
explanation: >-
Evidences the non-constancy asserted in this phenotype's description: a
genetically confirmed patient tested with normal hearing. Graded SUPPORT,
not REFUTE. `supports` is claim-relative in principle, but it is consumed
- `hpoa_export` maps REFUTE to the HPOA `NOT` qualifier, which asserts the
phenotype is excluded from the disease, and that is false here and
contradicts the positive row from the IUIS classification. Incomplete
penetrance belongs in the frequency column, and genuine absence would be
`frequency: EXCLUDED` instead.
notes: >-
The mechanism connecting an SRP targeting defect to cochlear pathology is
unknown, so this phenotype is deliberately left unattached to the causal
chain rather than conformed to a hair-cell module - see the
`srp72-deafness-mechanism` discussion.
animal_models:
- name: Srp72 heterozygous null mouse
species: Mouse
genotype: Srp72+/- (null allele, heterozygous)
publication: PMID:31254415
description: >-
A germline Srp72 null mouse built specifically to test whether a reduced
SRP72 dose explains the human marrow phenotype. It does not: heterozygotes
have no haematological disorder. The model is curated here because that
negative result is informative - it is the main argument against simple
haploinsufficiency as the human lesion - and because its one positive
finding, a transcriptional fall in secreted factors, is the most concrete
mechanistic lead anyone has offered for the tissue restriction.
modeled_mechanisms:
- target: Bone marrow hypocellularity
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
Halving Srp72 dose in mice does not produce marrow failure or any
haematological disorder.
limitations: >-
The model tests gene dosage only. Both human alleles are point/frameshift
variants whose protein mislocalizes and, for one, fails to associate with
7SL RNA, so a null heterozygote may simply not be the right model of the
human lesion. Mouse and human haematopoietic demand and lifespan also
differ, and the animals were not aged or stressed to unmask a phenotype.
readouts:
- name: Blood and bone marrow cellularity
target: Bone marrow hypocellularity
direction: DECREASED
interpretation: >-
Mild reductions only, without marrow failure - a quantitative shift far
short of the human phenotype.
evidence:
- reference: PMID:31254415
reference_title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Heterozygous loss of Srp72 in mice is not associated with major changes in hematopoiesis, although causes mild reductions in blood and BM cellularity and minor changes within the stem/progenitor compartment. We did not observe any hematological disorder."
explanation: >-
Reports the cellularity measurement and the absence of a
haematological disorder in the same result.
evidence:
- reference: PMID:31254415
reference_title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
supports: REFUTE
directness: DIRECT
evidence_source: MODEL_ORGANISM
snippet: "The Srp72+/- mouse model only partially recapitulates the phenotype observed in families with inherited SRP72 lesions."
explanation: >-
The authors' own assessment that the model does not reproduce the human
disease. Graded REFUTE against the proposition that reduced Srp72 dosage
is sufficient for marrow failure.
- target: Impaired Haematopoietic Output
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
The model does show a change in the stem/progenitor compartment and a
transcriptional fall in secreted factors, which is a partial correlate of
reduced haematopoietic output even though no disease results.
limitations: >-
The expression change is transcriptional and was not shown to cause the
cellularity change, nor was the secretome measured at protein level.
readouts:
- name: Expression of genes encoding secreted factors, cytokines and receptors
target: Impaired Haematopoietic Output
direction: DECREASED
interpretation: >-
The most concrete mechanistic lead available for how an SRP defect could
act selectively on haematopoiesis - via the secreted proteome, which is
exactly the cargo class SRP handles.
evidence:
- reference: PMID:31254415
reference_title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Interestingly, gene expression analysis demonstrated that genes encoding secreted factors, including cytokines and receptors, were transcriptionally down-regulated in Srp72+/- animals."
explanation: >-
Reports the direction and the class of transcripts affected.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Six families as of March 2024, and a seventh reported in the citing paper.
No rate is set: a case count is not a population rate, and the source says
in the same paragraph that the undiagnosed fraction cannot be estimated.
evidence:
- reference: PMID:41472573
reference_title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "BMFS1 is very rare, with only six families reported as of March 2024"
explanation: >-
The only quantified statement of how many BMFS1 families are on record,
which is what `CASES_IN_LITERATURE` is for.
treatments:
- name: Haematopoietic Stem Cell Transplantation
description: >-
Allogeneic HSCT is the only treatment that replaces the failing marrow
compartment, and is the definitive management of the marrow failure and
clonal-evolution risk. Two grades of evidence are cited below. The
BMFS1-specific outcomes are DIRECT: of the previously reported cases only
two were transplanted, one doing well and one lost to acute immune
rejection, and the 2026 index case was transplanted from a sibling with
normal counts by day 132. The GeneReviews referral pathway is INDIRECT,
stated for the monosomy 7 predisposition class whose Table 2 of
predisposing disorders includes SRP72 / bone marrow failure syndrome 1.
The transplant denominator is what matters clinically here: with three
transplanted patients in the whole literature, one of whom died of
rejection, this is a treatment of established intent and almost no outcome
base. Do not read the day-132 result as a success rate.
treatment_term:
preferred_term: Hematopoietic stem cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
therapeutic_modality: CELL_THERAPY
target_mechanisms:
- target: Bone marrow hypocellularity
description: >-
Transplantation replaces the failing haematopoietic compartment, acting
on the marrow-failure node rather than on the SRP lesion upstream of it.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK571103/
reference_title: "Monosomy 7 Predisposition Syndromes Overview - GeneReviews® - NCBI Bookshelf"
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "Measures include urgent referral to a hematologist for evaluation of cytopenias and bone marrow abnormalities that appear prior to the development of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and urgent referral to a hematopoietic stem cell transplantation (HSCT) specialist to identify potential donors and determine a transplant strategy."
explanation: >-
GeneReviews management guidance for the monosomy 7 predisposition
syndromes, the class whose Table 2 lists SRP72 / bone marrow failure
syndrome 1. Graded OTHER because it is expert management guidance rather
than a reported study result, and INDIRECT because it is stated for the
class rather than for BMFS1 specifically.
- reference: PMID:41472573
reference_title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Among the reported cases, only two patients underwent HSCT (Sakaguchi and Yoshida 2022; Tarlock et al. 2022). One had a good prognosis, while the other failed due to acute immune rejection."
explanation: >-
The entire prior transplant experience in BMFS1: two patients, one good
outcome and one death from acute immune rejection. DIRECT and
disease-specific, and the reason this entry does not present HSCT as a
settled outcome.
- reference: PMID:41472573
reference_title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "After the diagnosis of BMFS1 by genetic testing, the child received hematopoietic stem cell transplantation from a sibling. After 132 days post-transplantation, all parameters of the patient were within the normal range."
explanation: >-
A third transplanted BMFS1 patient with normal haematological parameters
at day 132 - short follow-up, and a single case, but disease-specific
evidence that transplantation corrects the marrow failure.
notes: >-
Supportive care is curated separately below rather than folded in here,
because the cited source states it as its own management limb with
transfusion thresholds.
- name: Supportive Transfusion and Infection Prophylaxis
description: >-
The standing management of the cytopenias while a transplant decision is
made, and the only management for a patient who is not a transplant
candidate. The cited source gives explicit transfusion thresholds - red
cells at about 80 g/L and platelets at or above 10 x 10^9/L - alongside
infection prevention. It does not treat the SRP lesion or the marrow
failure; it substitutes for the missing output.
treatment_term:
preferred_term: Supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Pancytopenia
term:
id: HP:0001876
label: Pancytopenia
evidence:
- reference: PMID:41472573
reference_title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Supportive treatment includes red cell transfusions (typically maintained at 80 g/L), platelet transfusions (maintained at ≥ 10 × 109/L), and infection prevention or anti-infection treatment"
explanation: >-
States the supportive-care limb for BMFS1 with its transfusion
thresholds. An earlier revision of this entry asserted no cached
reference stated this; that was wrong and is corrected here.
notes: >-
No `target_mechanisms` link: transfusion replaces the marrow's product
rather than acting on any node in the causal chain, so a mechanism edge
would overstate what it does.
discussions:
- discussion_id: srp72-molecular-lesion
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does the molecular lesion in SRP72 bone marrow failure differ by allele
class - the missense variants acting through a misassembling subunit that
interferes with the particle, and the frameshift and splice variants
through simple loss of function - or does one mechanism explain them all?
attaches_to:
- pathophysiology#SRP72 Deficiency
- genetic#SRP72
rationale: >-
The evidence pulls both ways, and the likeliest reconciliation is that the
answer is allele-dependent.
Against simple haploinsufficiency, for the founding missense alleles: the
mutant proteins mislocalize and one fails to associate with 7SL RNA, which
is an assembly defect rather than a reduced dose. The dosage-only mouse
points the same way - halving Srp72 produces no haematological disorder at
all, so if dose alone were the lesion the model should be sick and is not.
For loss of function, in a different allele class: the later reported
variants are a frameshift whose in-vitro study is reported as loss of
function, and a splice variant producing a premature termination codon.
Those are the alleles a haploinsufficiency model fits.
So the question is no longer "which single mechanism", but whether the
missense and truncating alleles reach the same phenotype by different
routes. Deciding it needs the missense subunit tested against particles
containing wild-type SRP72 - the experiment nobody has reported. This is
exactly why `functional_impact_category` is left unset on `genetic#SRP72`:
the slot takes one value per variant context, and this entry curates the
gene rather than the individual alleles, so any single value would erase
the split the evidence suggests.
evidence:
- reference: PMID:22541560
reference_title: "Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants."
explanation: >-
Variant-specific failure of 7SL RNA association - an assembly defect
rather than a dosage effect, and the observation that opens this question.
- reference: PMID:31254415
reference_title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Heterozygous loss of Srp72 in mice is not associated with major changes in hematopoiesis, although causes mild reductions in blood and BM cellularity and minor changes within the stem/progenitor compartment. We did not observe any hematological disorder."
explanation: >-
The dosage-only model does not produce the disease, which is the
complementary argument against haploinsufficiency for the missense
alleles.
- reference: PMID:40922878
reference_title: "A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "In vitro functional studies indicated a loss-of-function mechanism."
explanation: >-
The other direction, for a frameshift allele: functional study reported
as loss of function, which is what a haploinsufficiency model predicts
and what the missense data argue against.
- reference: PMID:41472573
reference_title: "A De Novo Splicing Mutation of SRP72 in Bone Marrow Failure Syndrome Type 1: Case Report and Review of the Literature."
supports: SUPPORT
directness: DIRECT
evidence_source: IN_VITRO
snippet: "This is predicted to result in a frameshift variant (p.Leu502ValfsTer14), which alters the amino acids and derives a premature termination codon."
explanation: >-
A second truncating allele, from a splice variant. A premature
termination codon is the canonical loss-of-function lesion, reinforcing
that the truncating and missense alleles may not share a mechanism.
Graded IN_VITRO because the sentence reports the readout of a minigene
splicing assay rather than a clinical observation, matching the sibling
in-vitro item above. Note the source's own hedge - the frameshift is
predicted from the observed 2-base retention, not directly demonstrated
at the protein level.
- discussion_id: srp72-mouse-model-mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
The Srp72+/- mouse has no haematological disorder, while heterozygous SRP72
variants cause marrow failure in humans. Is the mouse a poor model of the
human lesion, or is reduced SRP72 dosage genuinely not the human mechanism?
attaches_to:
- animal_models#Srp72 heterozygous null mouse
- pathophysiology#SRP72 Deficiency
rationale: >-
Evidence exists in the model and its translational validity is the open
question, which is what distinguishes this from a plain KNOWLEDGE_GAP. The
two readings have different consequences. If the mouse is simply the wrong
construct - a null allele where the human alleles make a misassembling
protein - then the human lesion is allele-specific and a knock-in of a human
variant should reproduce it. If instead dosage really is insufficient in
both species, the human phenotype needs a second factor, which would also
help explain the unaffected carriers. The decisive experiment is a knock-in
of a human SRP72 allele rather than a null.
evidence:
- reference: PMID:31254415
reference_title: "Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes."
supports: SUPPORT
directness: DIRECT
evidence_source: MODEL_ORGANISM
snippet: "The Srp72+/- mouse model only partially recapitulates the phenotype observed in families with inherited SRP72 lesions."
explanation: >-
The authors state the mismatch themselves.
- discussion_id: srp72-tissue-restriction
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does a defect in the signal recognition particle - a housekeeping
complex required by every nucleated cell - produce a phenotype largely
restricted to haematopoiesis and hearing?
attaches_to:
- pathophysiology#Impaired SRP-Dependent Cotranslational Protein Targeting
rationale: >-
This is the load-bearing unexplained step of the whole pathograph. Without
it, the edge from impaired co-translational targeting to impaired
haematopoietic output is an assertion of tissue selectivity that no source
accounts for. The cited review makes the same point about the SRP and
ribosome biogenesis disorders as a class.
evidence:
- reference: PMID:37226705
reference_title: "Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants."
supports: SUPPORT
evidence_source: OTHER
snippet: "How these fundamental and ubiquitous cellular processes that lead to protein synthesis result in specific, limited phenotypes remains poorly understood."
explanation: >-
States the gap explicitly for the class of disorders this one belongs to.
- discussion_id: srp72-deafness-mechanism
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
By what mechanism does SRP72 deficiency cause congenital sensorineural
deafness, and why is the deafness present in some reported families and
absent in others?
attaches_to:
- phenotypes#Congenital sensorineural hearing impairment
rationale: >-
The deafness is recorded as a feature of the syndrome but has no proposed
mechanistic route from the SRP lesion, and it does not segregate with the
haematologic phenotype across all reported families. Conforming it to a
hair-cell degeneration module would assert a mechanism nobody has shown, so
it is left as an unexplained phenotype instead.
- discussion_id: srp72-penetrance
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What is the penetrance of a heterozygous SRP72 variant for bone marrow
failure or myelodysplasia, and is a second hit or modifier required?
attaches_to:
- genetic#SRP72
- inheritance#Autosomal dominant
rationale: >-
Autosomal dominant inheritance is recorded, but the number of reported
families is small and the literature includes transmission from an
unaffected parent and reports in which an SRP72 variant is one of several
variants of uncertain significance. Whether the allele is fully penetrant is
therefore open. No penetrance value is set on the `inheritance` block for
this reason.
evidence:
- reference: PMID:40922878
reference_title: "A 14-Year-Old Male Patient With Bone Marrow Failure Syndrome, Without Deafness, Caused by a Novel SRP72 Mutation Inherited From His Father: A Case Report."
supports: SUPPORT
directness: DIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Despite this, only the 14-year-old patient in the family developed pancytopenia, while his asymptomatic father, who carries the same mutation, remains healthy."
explanation: >-
A documented carrier of the same variant who is unaffected, which is
direct evidence of incomplete penetrance.
- discussion_id: srp72-evidence-completeness
kind: CURATION_TODO
status: OPEN
prompt: >-
Re-curate this entry against the primary SRP72 literature once those
references can be fetched into `references_cache/`.
rationale: >-
Largely discharged. The entry was first written in a session with no network
route to PubMed, so it cited only an expert classification table, a review of
a neighbouring disorder, and a GeneReviews overview. Egress later opened and
the primary literature was fetched and curated: the founding exome study
(PMID:22541560) now supports the gene, the inheritance, the molecular lesion
and the co-translational-targeting node; the Srp72 heterozygous-null mouse
(PMID:31254415) is curated in `animal_models` with a
`FAILS_TO_RECAPITULATE` link and its own `HUMAN_MODEL_MISMATCH` discussion;
and incomplete penetrance is cited from PMID:40922878.
What remains: the per-variant allele spectrum from PMID:41472573 is not
curated as `variants` entries, though the paper's review table is the best
available source for it and the entry now cites the paper for treatment,
prevalence and the truncating-allele lesion; the SRP72 structural work
(PMID:27899666) is cached but not yet used, and would let the two molecular
sub-lesions - SRP68 heterodimerization versus 7SL RNA binding - be split
into separate nodes; the genome-first
penetrance cohort (PMID:39501104) is cached and could quantify penetrance,
but reports a pooled odds ratio across eight genes and no SRP72-specific
figure, so it must not be cited as an SRP72 penetrance estimate.
notes: >-
Scope and evidence limits, stated plainly so the gaps are not mistaken for
findings.
This entry was first written in a session whose egress policy blocked every
literature source - PubMed/E-utilities, Europe PMC, PMC, Crossref,
ClinicalTrials.gov, Orphadata and OLS all returned 403 at the agent proxy - so
it initially cited only what was already in `references_cache/`: an expert
classification table (IUIS 2022), a review of Shwachman-Diamond syndrome, and
a GeneReviews overview. Egress later opened in the same session and the
primary literature was fetched and curated, so that constraint no longer
describes the entry. It is recorded here because it explains the shape of the
history records and of the early review rounds, and because the residual gaps
it caused are listed in the `srp72-evidence-completeness` discussion.
No `frequency` bands are set on any phenotype. The published series are a
handful of families with different alleles, and the congenital deafness in
particular is present in some and absent in others; a band pooled across them
would assert a population frequency the sources do not support. Numbers, when
added, should name their denominator.
The `prevalence` record is a case count, not a rate. Six families as of March
2024 is the only quantified figure any cited source gives, so `measure_type`
is `CASES_IN_LITERATURE` and no `rate_per_100000` is set - the source itself
says the undiagnosed fraction cannot be determined. An earlier revision of
this entry said no prevalence figure was citable at all; that was wrong, and
it was a claim about a file this same change set had already committed.
One treatment is curated, and its evidence is deliberately class-level. The
cached GeneReviews monosomy 7 overview - whose Table 2 of predisposing
disorders includes SRP72 / bone marrow failure syndrome 1 - states the HSCT
referral pathway for that class, so the transplant claim is cited with
`directness: INDIRECT` rather than left out. An earlier revision of this entry
asserted that nothing in the cached references bore on treatment at all; that
overstated the constraint and was corrected in review. Supportive transfusion
and infection prophylaxis remain uncurated because no cached reference states
them in quotable form.