Rhabdomyolysis Susceptibility To 1

Mendelian MONDO:0859371 Pathograph 14 Show in embeddings browser Rhabdomyolysis Metabolic and Structural Myopathy

Rhabdomyolysis susceptibility 1 (RHABDO1) is an autosomal recessive predisposition to recurrent, often severe rhabdomyolysis caused by biallelic loss-of-function variants in OBSCN. OBSCN encodes obscurin, a giant sarcomeric scaffold protein that binds titin and myomesin at the M-band and, through its C-terminus, the sarcoplasmic reticulum anchor small ankyrin-1 (sAnk1.5) and ankyrin-B. Patients are usually well between attacks. Episodes begin in childhood or adolescence and are set off mainly by high-intensity exercise, sometimes by fever. They bring myalgia, cramps, very high serum creatine kinase, myoglobinuria and, in some cases, acute kidney injury. Patient muscle has little or no obscurin, and patient myoblasts lose more sarcoplasmic reticulum calcium under metabolic stress than control cells. Obscurin-knockout mice have a disorganized longitudinal sarcoplasmic reticulum, mislocalized ankyrin-B and dystrophin, a fragile sarcolemma, and exercise-induced muscle damage. No affected patient has had cardiomyopathy, although OBSCN variants have been reported in inherited cardiomyopathies. Penetrance is incomplete: a sibling carrying the same biallelic variants can remain free of rhabdomyolysis.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry biallelic (homozygous or compound heterozygous) loss-of-function OBSCN variants. Penetrance is incomplete: rhabdomyolysis also needs an environmental trigger, and a sibling with the same genotype has been reported without it.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34957489 SUPPORT Human clinical
"We identified 10 bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis."
Disease alleles are biallelic in every proband of the founding series.
PMID:41645489 SUPPORT BACKGROUND Human clinical
"Interestingly, a sibling with the same biallelic OBSCN variants has not presented with rhabdomyolysis."
Records incomplete penetrance in a previously reported family. The sentence restates an earlier report rather than this paper's own patient.
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Discussions and Knowledge Gaps

1
Why does obscurin loss cause trigger-dependent recurrent rhabdomyolysis in people, when obscurin-knockout mice show at most mild, mainly diaphragmatic exercise injury and no frank rhabdomyolysis?
HUMAN MODEL MISMATCH OPEN rhabdo1_mouse_model_mismatch
Attached to
pathophysiology#Sarcolemmal Fragility pathophysiology#Exercise-Induced Myofiber Breakdown animal_models#Obscurin knockout mouse
The membrane and sarcoplasmic reticulum defects proposed for the human disease come mainly from mice, where the paralog Obsl1 compensates for obscurin loss and the single knockout is mild. The only human functional readout is reduced sarcoplasmic reticulum calcium in starved patient myoblasts. Whether OBSL1 compensates less in human skeletal muscle, or the human trigger load is simply larger, is untested.
Show evidence (1 reference)
PMID:31098411 SUPPORT Model organism
"skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts"
Single obscurin knockout mice are mild, unlike the human disease.
⚙

Pathophysiology

5
Obscurin Loss of Function
Biallelic truncating OBSCN variants reduce the transcript and remove obscurin protein from skeletal muscle. Obscurin normally binds titin and myomesin at the M-band, and through its C-terminus binds the sarcoplasmic reticulum protein sAnk1.5 and ankyrin-B, linking the myofibril to the sarcoplasmic reticulum and to the subsarcolemmal cytoskeleton.
OBSCN hgnc:15719 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves OBSCN (hgnc:15719). hgnc:15719 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
ankyrin binding GO:0030506 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ankyrin binding (GO:0030506). GO:0030506 is a molecular function from the Gene Ontology.
Downstream
Longitudinal Sarcoplasmic Reticulum Disorganization
Sarcolemmal Fragility
Exercise-Induced Sarcomeric M-Band Disorganization
Show evidence (3 references)
PMID:34957489 SUPPORT Human clinical
"We show reduced expression of OBSCN and loss of obscurin protein in patient muscle."
Obscurin is lost from patient muscle.
PMID:41645489 SUPPORT Human clinical
"OBSCN transcript levels were significantly decreased in the patient's muscle"
A frameshift allele lowers OBSCN transcript in patient muscle, consistent with nonsense-mediated decay.
PMID:12527750 SUPPORT In vitro / ex vivo
"We report here that ank1.5, a small splice variant of the ank1 gene localized on the sarcoplasmic reticulum membrane, is capable of interacting with a sequence of 25 aa located at the COOH terminus of obscurin."
Normal function: the obscurin C-terminus binds the sarcoplasmic reticulum ankyrin sAnk1.5, the binding activity bound on this node.
Longitudinal Sarcoplasmic Reticulum Disorganization
Without its obscurin anchor, sAnk1.5 is lost or mislocalized and the longitudinal sarcoplasmic reticulum around the myofibril is disorganized. In patient myoblasts the reticulum holds less calcium than control cells under starvation, which the authors attribute to less efficient calcium re-uptake or storage when metabolism is limited.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
calcium ion import into sarcoplasmic reticulum GO:1990036 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion import into sarcoplasmic reticulum (GO:1990036). GO:1990036 is a biological process from the Gene Ontology.
Downstream
Exercise-Induced Myofiber Breakdown
Show evidence (2 references)
PMID:34957489 SUPPORT INDIRECT In vitro / ex vivo
"Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts."
Patient cells hold less calcium in the sarcoplasmic reticulum under metabolic stress. Graded INDIRECT because reduced uptake is the authors' inference from reduced content.
PMID:19584095 SUPPORT Model organism
"Lack of obscurin in cross-striated muscles leads to changes in longitudinal SR architecture and disruption of small ankyrin-1.5 (sAnk1.5) expression and localization."
Structural change in the reticulum in obscurin-knockout mice.
Sarcolemmal Fragility
Obscurin targets ankyrin-B to the M-band. Without it, dystrophin is mislocalized at costameres, the subsarcolemmal microtubule network is disrupted, and the sarcolemma becomes fragile, so exercise damages the membrane more than in wild-type muscle. Shown in knockout mice; patient muscle shows reduced ankyrin-1 and ankyrin-2 by proteomics.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Animal models
Obscurin knockout mouse Mouse recapitulates The knockout shows the membrane fragility and exercise intolerance proposed to underlie the human disease.
Downstream
Exercise-Induced Myofiber Breakdown
Show evidence (3 references)
PMID:23420875 SUPPORT Model organism
"these mutant mice displayed marked sarcolemmal fragility and reduced muscle exercise tolerance"
Obscurin-knockout mice have a fragile sarcolemma and poor exercise tolerance.
PMID:41645489 SUPPORT Human clinical
"In contrast, the decreased proteins impact extrasarcomeric cytoskeleton processes (ANK1 and ANK2)"
Patient muscle has less ankyrin-1 and ankyrin-2, the obscurin partners that link the myofibril to membranes.
PMID:31098411 SUPPORT INDIRECT Model organism
"Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization."
Obscurin acts in sarcolemmal stability, but in this study the effect was clear only when its paralog Obsl1 was also removed. Graded INDIRECT because the double knockout is not the human genotype.
Exercise-Induced Sarcomeric M-Band Disorganization
Under intense mechanical load, obscurin-deficient fibers lose the regular M-band and H-zone structure of the sarcomere. Patient muscle shows myofibrillar disintegration with M- and Z-band disruption and core-like central lesions containing desmin aggregates.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Animal models
Obscurin knockout mouse Mouse partially recapitulates
Downstream
Exercise-Induced Myofiber Breakdown
Show evidence (2 references)
PMID:27784675 SUPPORT Model organism
"electron microscopy revealed that, in the diaphragm of exercised obscurin KO mice, but not in the hindlimb muscles, both M-line and H-zone of sarcomeres appeared wavy and less defined"
Exercise disorganizes the M-band in obscurin-knockout diaphragm.
PMID:41645489 SUPPORT Human clinical
"disruption of the myofibrillar structure with disruption of the M‐ and Z‐bands"
The same ultrastructural lesion in a patient biopsy.
Exercise-Induced Myofiber Breakdown
Intense exercise, and sometimes fever, triggers breakdown of obscurin-deficient myofibers. Their contents, including creatine kinase and myoglobin, leak into the blood, producing rhabdomyolysis.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Exercise-induced rhabdomyolysis
Elevated circulating creatine kinase activity
Myoglobinuria
Exercise-induced myalgia
Show evidence (1 reference)
PMID:38159459 SUPPORT Human clinical
"Obscurin-deficient muscle fibers seem to have increased susceptibility to damage triggered by exercise that may lead to rhabdomyolysis."
The authors' reading of their two patients: exercise damages obscurin-deficient fibers.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Rhabdomyolysis Susceptibility To 1 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

8
Genitourinary 2
Myoglobinuria HP:0002913 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoglobinuria (HP:0002913). HP:0002913 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38159459 SUPPORT Human clinical
"Here we reported two young patients with a history of cramps, myalgia, exercise intolerance, rhabdomyolysis, and myoglobinuria"
Myoglobinuria in both patients of this report.
Acute kidney injury FREQUENT HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"Renal failure occurred in 3 patients (3/9), but cardiac function was normal in all patients."
Kidney injury in a third of reported patients; no cardiac involvement.
Metabolism 1
Elevated circulating creatine kinase activity VERY_FREQUENT HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"All patients presented with significant elevation of serum CK (mean value over 275,000 IU/L and maximum up to 603,000 IU/L)"
Marked creatine kinase elevation in all nine reported patients.
Musculoskeletal 3
Exercise-induced rhabdomyolysis VERY_FREQUENT HP:0009045 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise-induced rhabdomyolysis (HP:0009045), qualified as juvenile onset. HP:0009045 is a phenotype from the Human Phenotype Ontology.
Onset: JUVENILE
Show evidence (2 references)
PMID:34957489 SUPPORT Human clinical
"Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years"
Recurrent rhabdomyolysis is the defining feature of the founding series.
PMID:40186404 SUPPORT Human clinical
"The main feature for these patients was childhood or adolescent onset, with exercise‐ or heat‐induced rhabdomyolysis"
Summary of the nine patients reported to date.
Exercise-induced muscle cramps HP:0003710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise-induced muscle cramps (HP:0003710). HP:0003710 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34957489 SUPPORT Human clinical
"other features included a history of myalgia and muscle cramps"
Cramps are part of the phenotype in the founding series.
PMID:41645489 SUPPORT Human clinical
"Patients harbouring biallelic OBSCN nonsense variants can also present with exercise‐induced cramps and myalgia, as observed in our patient without developing the full clinical picture of rhabdomyolysis"
Exercise-induced cramps, sometimes without rhabdomyolysis.
Increased variability in muscle fiber diameter HP:0003557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased variability in muscle fiber diameter (HP:0003557). HP:0003557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41645489 SUPPORT REVIEW SYNTHESIS Human clinical
"Previous studies of OBSCN‐associated myopathy revealed variable muscle pathology, including increased variation in muscle fibre size, internalised nuclei, ring fibres, necrotic fibres, predominance of type 2 muscle fibres and core‐like pathology"
Summarizes biopsy findings across earlier reports.
Constitutional 2
Exercise-induced myalgia VERY_FREQUENT HP:0003738 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise-induced myalgia (HP:0003738). HP:0003738 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40186404 SUPPORT Human clinical
"accompanied by exercise intolerance (7/9) and myalgia (8/9)"
Myalgia in eight of nine reported patients.
PMID:41645489 SUPPORT Human clinical
"We present a 22‐year‐old woman who experienced muscle stiffness, myalgia and cramps in her thighs and gluteal muscles after performing high‐intensity sports (roundnet)."
Exercise-induced myalgia in a patient with biallelic variants.
Exercise intolerance FREQUENT HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"accompanied by exercise intolerance (7/9) and myalgia (8/9)"
Exercise intolerance in seven of nine reported patients.
🧬

Genetic Associations

1
OBSCN (Causal)
Gene: OBSCN hgnc:15719 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is OBSCN (hgnc:15719). hgnc:15719 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:34957489 SUPPORT Human clinical
"We show reduced expression of OBSCN and loss of obscurin protein in patient muscle."
The patient alleles abolish obscurin in skeletal muscle, consistent with loss of function.
PMID:38159459 SUPPORT Human clinical
"Here we reported two young patients with a history of cramps, myalgia, exercise intolerance, rhabdomyolysis, and myoglobinuria without any evidence of concomitant cardiomyopathy in association with novel OBSCN variants (c.24822C>A and c.2653+1G>C)."
An independent report of two further patients with OBSCN variants and the same phenotype.
PMID:40186404 SUPPORT Human clinical
"The patient carried compound heterozygous variants, including c.21184C>T (nonsense variant) and c.15610+12C>T (intronic splicing variant)."
A further compound heterozygous case, from China.
+ 2 more references
Variants (1)
p.Gln7062*
NM_001386125.1:c.21184C>T, a nonsense variant found in trans with the intronic c.15610+12C>T in an 11-year-old girl with exercise-induced rhabdomyolysis. Her mother, homozygous for c.21184C>T, had exercise-induced myalgia and a creatine kinase over 2000.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"The fact that the mother harbored the homozygous OBSCN variant and also showed symptoms of exercise-induced myalgia provides further support for its pathogenicity."
A homozygous carrier of the nonsense allele is also symptomatic.
💊

Medical Actions

2
Fluid therapy during acute rhabdomyolysis
Action: Fluid TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fluid Therapy (NCIT:C116537). NCIT:C116537 is a clinical intervention from the NCI Thesaurus. NCIT:C116537
Platform: Other
There is no OBSCN-directed therapy. Acute episodes are treated as for other causes of rhabdomyolysis, with intravenous fluids and urine alkalinization to protect the kidneys.
Target Phenotypes: Exercise-induced rhabdomyolysis HP:0009045 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Exercise-induced rhabdomyolysis (HP:0009045). HP:0009045 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"The patient received routine pediatric care, including urine alkalinization, fluid replacement, and antioxidant therapy with vitamin C. Her symptoms significantly improved after five days of treatment"
Supportive fluid treatment of an acute episode, in one patient.
Avoidance of strenuous exercise
Action: Exercise CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Exercise Counseling (NCIT:C101235). NCIT:C101235 is a clinical intervention from the NCI Thesaurus. NCIT:C101235
Platform: Behavioral / lifestyle
Patients are advised to avoid strenuous physical activity, the main trigger of episodes. No controlled study of this has been reported.
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"given the persistently high CK levels, she was advised to avoid strenuous physical activity"
Trigger avoidance was advised in this case.
🌍

Environmental Factors

1
Strenuous exercise
exposure to strenuous exercise ECTO:6000031 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to strenuous exercise (ECTO:6000031). ECTO:6000031 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
High-intensity exercise is the main trigger of rhabdomyolysis episodes. Fever and heat are less common triggers.
Show evidence (1 reference)
PMID:41645489 SUPPORT Human clinical
"Symptoms are mainly induced by high-intensity sports."
High-intensity exercise triggers symptoms.
Mechanism Target:
TRIGGERS Exercise-Induced Myofiber Breakdown — Intense exercise precipitates fiber breakdown in obscurin-deficient muscle.
Show evidence (1 reference)
PMID:41645489 SUPPORT Human clinical
"In the majority of these patients, cramps, myalgia and rhabdomyolysis were triggered by high‐intensity sports"
Exercise triggers the episodes in most reported patients.
🔬

Diagnosis

1
Exome sequencing
Reported cases were found by exome or panel sequencing of patients with recurrent rhabdomyolysis.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40186404 SUPPORT Human clinical
"We performed whole exome sequencing on a patient with exercise-induced rhabdomyolysis to identify possible causative gene variants."
Diagnosis by exome sequencing.
🐁

Animal Models

1
Obscurin knockout mouse
Obscn-null mice have a disorganized longitudinal sarcoplasmic reticulum, mislocalized ankyrin-B and dystrophin, sarcolemmal fragility, reduced running endurance and exercise-induced muscle damage, worst in the diaphragm and with age.
Species
Mouse
Genotype
Obscn-/-
Publication
PMID:23420875
Pathograph links
Sarcolemmal Fragility recapitulates fidelity: moderate observes: tissue The knockout shows the membrane fragility and exercise intolerance proposed to underlie the human disease.
Limitations: Frank rhabdomyolysis with myoglobinuria has not been reported in the mouse. Exercise injury is most marked in the diaphragm, not the limb muscles affected in patients.
Show evidence (1 reference)
PMID:23420875 SUPPORT Model organism
"these mutant mice displayed marked sarcolemmal fragility and reduced muscle exercise tolerance"
The knockout reproduces the fragility node.
Exercise-Induced Sarcomeric M-Band Disorganization partially recapitulates fidelity: moderate observes: tissue
Limitations: Seen in the diaphragm but not the hindlimb muscles of exercised mice.
Show evidence (1 reference)
PMID:27784675 SUPPORT Model organism
"electron microscopy revealed that, in the diaphragm of exercised obscurin KO mice, but not in the hindlimb muscles, both M-line and H-zone of sarcomeres appeared wavy and less defined"
M-band disorganization after exercise, limited to the diaphragm.
{ }

Source YAML

click to show 
name: Rhabdomyolysis Susceptibility To 1
creation_date: "2026-10-27T18:02:59Z"
category: Mendelian
synonyms:
- RHABDO1
- OBSCN-related rhabdomyolysis
- OBSCN-related exercise intolerance
description: >-
  Rhabdomyolysis susceptibility 1 (RHABDO1) is an autosomal recessive
  predisposition to recurrent, often severe rhabdomyolysis caused by biallelic
  loss-of-function variants in OBSCN. OBSCN encodes obscurin, a giant
  sarcomeric scaffold protein that binds titin and myomesin at the M-band and,
  through its C-terminus, the sarcoplasmic reticulum anchor small ankyrin-1
  (sAnk1.5) and ankyrin-B. Patients are usually well between attacks. Episodes
  begin in childhood or adolescence and are set off mainly by high-intensity
  exercise, sometimes by fever. They bring myalgia, cramps, very high serum
  creatine kinase, myoglobinuria and, in some cases, acute kidney injury.
  Patient muscle has little or no obscurin, and patient myoblasts lose more
  sarcoplasmic reticulum calcium under metabolic stress than control cells.
  Obscurin-knockout mice have a disorganized longitudinal sarcoplasmic
  reticulum, mislocalized ankyrin-B and dystrophin, a fragile sarcolemma, and
  exercise-induced muscle damage. No affected patient has had cardiomyopathy,
  although OBSCN variants have been reported in inherited cardiomyopathies.
  Penetrance is incomplete: a sibling carrying the same biallelic variants
  can remain free of rhabdomyolysis.
disease_term:
  preferred_term: rhabdomyolysis, susceptibility to, 1
  term:
    id: MONDO:0859371
    label: rhabdomyolysis, susceptibility to, 1
parents:
- Rhabdomyolysis
- Metabolic and Structural Myopathy
notes: >-
  Scope: biallelic OBSCN loss of function predisposing to rhabdomyolysis,
  matching MONDO:0859371 (OMIM:620235). The human evidence is a small number
  of probands: six in the founding series (PMID:34957489), two in
  PMID:38159459, and single cases in PMID:40186404, PMID:40813169 and
  PMID:41645489. PMID:40186404 counts nine patients and fourteen variants
  reported to that date. The mechanism nodes on sarcoplasmic reticulum
  architecture and sarcolemmal fragility rest on obscurin-knockout mice; the
  human evidence for them is reduced sarcoplasmic reticulum calcium content in
  patient myoblasts and the proteomic and ultrastructural findings in one
  biopsy (PMID:41645489). Heterozygous OBSCN variants, mostly missense, are
  reported in hypertrophic and dilated cardiomyopathy and left ventricular
  noncompaction. That is a different, mainly dominant and contested
  association, and it is not recorded here. No GeneReviews chapter and no
  prevalence figure were found.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic (homozygous or compound
    heterozygous) loss-of-function OBSCN variants. Penetrance is incomplete:
    rhabdomyolysis also needs an environmental trigger, and a sibling with
    the same genotype has been reported without it.
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 10 bi-allelic loss-of-function variants in the gene
      encoding obscurin (OBSCN) predisposing individuals to recurrent
      rhabdomyolysis.
    explanation: >-
      Disease alleles are biallelic in every proband of the founding series.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Interestingly, a sibling with the same biallelic OBSCN variants has not
      presented with rhabdomyolysis.
    explanation: >-
      Records incomplete penetrance in a previously reported family. The
      sentence restates an earlier report rather than this paper's own
      patient.
genetic:
- name: OBSCN
  gene_term:
    preferred_term: OBSCN
    term:
      id: hgnc:15719
      label: OBSCN
  association: Causal
  relationship_type: CAUSATIVE
  notes: >-
    Reported alleles are mostly nonsense, frameshift and splice variants. The
    founding series describes 10 variants in six patients (PMID:34957489).
    Missense alleles have been reported only in trans with a null allele
    (PMID:41645489, p.Ala4864Asp, classified there as a VUS). OBSCN
    missense variants are hard to interpret: the cardiomyopathy-associated
    p.Arg4344Gln is carried by 15% of African Americans and did not change
    titin binding or domain stability in vitro (PMID:33438037). No ClinGen
    gene-disease validity assertion for OBSCN and rhabdomyolysis was found in
    the local cache, so no validity tier is recorded.
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show reduced expression of OBSCN and loss of obscurin protein in
      patient muscle.
    explanation: >-
      The patient alleles abolish obscurin in skeletal muscle, consistent
      with loss of function.
  - reference: PMID:38159459
    reference_title: "Novel OBSCN variants associated with a risk to exercise-intolerance and rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we reported two young patients with a history of cramps, myalgia,
      exercise intolerance, rhabdomyolysis, and myoglobinuria without any
      evidence of concomitant cardiomyopathy in association with novel OBSCN
      variants (c.24822C>A and c.2653+1G>C).
    explanation: >-
      An independent report of two further patients with OBSCN variants and
      the same phenotype.
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient carried compound heterozygous variants, including
      c.21184C>T (nonsense variant) and c.15610+12C>T (intronic splicing
      variant).
    explanation: >-
      A further compound heterozygous case, from China.
  - reference: PMID:40813169
    reference_title: "Rhabdomyolysis associated with OBSCN mutations: case report and mechanistic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a young adult male with recurrent episodes of muscle pain and
      cramping, in whom genetic testing identified two heterozygous OBSCN
      variants (c.20292C>A and c.708del).
    explanation: >-
      A further patient with two OBSCN variants (a nonsense and a frameshift)
      and recurrent exertional muscle symptoms.
  - reference: PMID:33438037
    reference_title: "When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: >-
      We found no changes in titin binding and thermostability for both
      variants and modestly increased affinities of PLN for R4344Q and R4444W.
    explanation: >-
      Does not bear on the loss-of-function claim of this record. It is cited
      as the source for the caution in the notes that OBSCN missense variants
      should not be assumed pathogenic: two cardiomyopathy-associated
      missense variants left titin binding and domain stability unchanged.
  variants:
  - name: p.Gln7062*
    description: >-
      NM_001386125.1:c.21184C>T, a nonsense variant found in trans with the
      intronic c.15610+12C>T in an 11-year-old girl with exercise-induced
      rhabdomyolysis. Her mother, homozygous for c.21184C>T, had
      exercise-induced myalgia and a creatine kinase over 2000.
    evidence:
    - reference: PMID:40186404
      reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The fact that the mother harbored the homozygous OBSCN variant and
        also showed symptoms of exercise-induced myalgia provides further
        support for its pathogenicity.
      explanation: >-
        A homozygous carrier of the nonsense allele is also symptomatic.
pathophysiology:
- name: Obscurin Loss of Function
  description: >-
    Biallelic truncating OBSCN variants reduce the transcript and remove
    obscurin protein from skeletal muscle. Obscurin normally binds titin and
    myomesin at the M-band, and through its C-terminus binds the sarcoplasmic
    reticulum protein sAnk1.5 and ankyrin-B, linking the myofibril to the
    sarcoplasmic reticulum and to the subsarcolemmal cytoskeleton.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: OBSCN
    term:
      id: hgnc:15719
      label: OBSCN
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: ankyrin binding
    modifier: DECREASED
    term:
      id: GO:0030506
      label: ankyrin binding
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show reduced expression of OBSCN and loss of obscurin protein in
      patient muscle.
    explanation: >-
      Obscurin is lost from patient muscle.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OBSCN transcript levels were significantly decreased in the patient's
      muscle
    explanation: >-
      A frameshift allele lowers OBSCN transcript in patient muscle,
      consistent with nonsense-mediated decay.
  - reference: PMID:12527750
    reference_title: "Binding of an ankyrin-1 isoform to obscurin suggests a molecular link between the sarcoplasmic reticulum and myofibrils in striated muscles."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We report here that ank1.5, a small splice variant of the ank1 gene
      localized on the sarcoplasmic reticulum membrane, is capable of
      interacting with a sequence of 25 aa located at the COOH terminus of
      obscurin.
    explanation: >-
      Normal function: the obscurin C-terminus binds the sarcoplasmic
      reticulum ankyrin sAnk1.5, the binding activity bound on this node.
  downstream:
  - target: Longitudinal Sarcoplasmic Reticulum Disorganization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19584095
      reference_title: "Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lack of obscurin in cross-striated muscles leads to changes in
        longitudinal SR architecture and disruption of small ankyrin-1.5
        (sAnk1.5) expression and localization.
      explanation: >-
        In knockout mice, loss of obscurin disorganizes the longitudinal
        sarcoplasmic reticulum.
  - target: Sarcolemmal Fragility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23420875
      reference_title: "Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In obscurin KO mice, localization at costameres of dystrophin, but not
        of β-dystroglycan, was altered, and the subsarcolemma microtubule
        cytoskeleton was disrupted.
      explanation: >-
        Without obscurin, ankyrin-B and dystrophin are mislocalized and the
        subsarcolemmal cytoskeleton is disrupted.
  - target: Exercise-Induced Sarcomeric M-Band Disorganization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27784675
      reference_title: "Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        obscurin is required for the maintenance of morphological and
        ultrastructural integrity of skeletal muscle fibers against damage
        induced by intense mechanical stress
      explanation: >-
        Without obscurin, sarcomere structure fails under intense exercise
        in mice.
- name: Longitudinal Sarcoplasmic Reticulum Disorganization
  description: >-
    Without its obscurin anchor, sAnk1.5 is lost or mislocalized and the
    longitudinal sarcoplasmic reticulum around the myofibril is disorganized.
    In patient myoblasts the reticulum holds less calcium than control cells
    under starvation, which the authors attribute to less efficient calcium
    re-uptake or storage when metabolism is limited.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: calcium ion import into sarcoplasmic reticulum
    modifier: DECREASED
    term:
      id: GO:1990036
      label: calcium ion import into sarcoplasmic reticulum
  notes: >-
    The calcium-uptake binding records the authors' interpretation of a
    reduced reticulum calcium content in starved patient myoblasts. Uptake
    was not measured directly, so the decrease is inferred.
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Patient cultured myoblasts appear more susceptible to starvation as
      evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content
      compared to control myoblasts.
    explanation: >-
      Patient cells hold less calcium in the sarcoplasmic reticulum under
      metabolic stress. Graded INDIRECT because reduced uptake is the
      authors' inference from reduced content.
  - reference: PMID:19584095
    reference_title: "Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lack of obscurin in cross-striated muscles leads to changes in
      longitudinal SR architecture and disruption of small ankyrin-1.5
      (sAnk1.5) expression and localization.
    explanation: >-
      Structural change in the reticulum in obscurin-knockout mice.
  downstream:
  - target: Exercise-Induced Myofiber Breakdown
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34957489
      reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        This likely reflects a lower efficiency when pumping Ca2+ back into
        the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic
        reticulum storage ability when metabolism is diminished.
      explanation: >-
        The authors propose that weaker calcium handling under metabolic load
        contributes to myofiber breakdown during exertion. The link to
        rhabdomyolysis is an inference, not a measurement.
- name: Sarcolemmal Fragility
  description: >-
    Obscurin targets ankyrin-B to the M-band. Without it, dystrophin is
    mislocalized at costameres, the subsarcolemmal microtubule network is
    disrupted, and the sarcolemma becomes fragile, so exercise damages the
    membrane more than in wild-type muscle. Shown in knockout mice; patient
    muscle shows reduced ankyrin-1 and ankyrin-2 by proteomics.
  biological_scale: CELLULAR
  conforms_to: "sarcolemmal_fragility_myofiber_necrosis#Sarcolemmal Mechanical Fragility"
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:23420875
    reference_title: "Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these mutant mice displayed marked sarcolemmal fragility and reduced
      muscle exercise tolerance
    explanation: >-
      Obscurin-knockout mice have a fragile sarcolemma and poor exercise
      tolerance.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, the decreased proteins impact extrasarcomeric cytoskeleton
      processes (ANK1 and ANK2)
    explanation: >-
      Patient muscle has less ankyrin-1 and ankyrin-2, the obscurin partners
      that link the myofibril to membranes.
  - reference: PMID:31098411
    reference_title: "Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Only deletion of both proteins and removal of their functional
      redundancy revealed their roles for sarcolemmal stability and
      sarcoplasmic reticulum organization.
    explanation: >-
      Obscurin acts in sarcolemmal stability, but in this study the effect
      was clear only when its paralog Obsl1 was also removed. Graded
      INDIRECT because the double knockout is not the human genotype.
  notes: >-
    The two mouse studies disagree on how much a single Obscn knockout
    shows. PMID:23420875 reports marked sarcolemmal fragility in obscurin
    knockouts, while PMID:31098411 describes the single knockout as benign
    and needed an Obsl1 co-deletion to reveal the membrane defect. OBSL1
    redundancy may also explain why patients are well between episodes.
  downstream:
  - target: Exercise-Induced Myofiber Breakdown
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23420875
      reference_title: "Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        these mutant mice displayed marked sarcolemmal fragility and reduced
        muscle exercise tolerance
      explanation: >-
        The fragile membrane is damaged by exercise in the knockout.
- name: Exercise-Induced Sarcomeric M-Band Disorganization
  description: >-
    Under intense mechanical load, obscurin-deficient fibers lose the regular
    M-band and H-zone structure of the sarcomere. Patient muscle shows
    myofibrillar disintegration with M- and Z-band disruption and core-like
    central lesions containing desmin aggregates.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:27784675
    reference_title: "Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      electron microscopy revealed that, in the diaphragm of exercised
      obscurin KO mice, but not in the hindlimb muscles, both M-line and
      H-zone of sarcomeres appeared wavy and less defined
    explanation: >-
      Exercise disorganizes the M-band in obscurin-knockout diaphragm.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      disruption of the myofibrillar structure with disruption of the M‐ and
      Z‐bands
    explanation: >-
      The same ultrastructural lesion in a patient biopsy.
  downstream:
  - target: Exercise-Induced Myofiber Breakdown
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27784675
      reference_title: "Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Histological analysis indicated that heavy exercise induced leukocyte
        infiltration, fibrotic connective tissue deposition, and
        hypercontractures in the diaphragm of KO mice.
      explanation: >-
        Exercise injures obscurin-deficient muscle in mice.
- name: Exercise-Induced Myofiber Breakdown
  description: >-
    Intense exercise, and sometimes fever, triggers breakdown of
    obscurin-deficient myofibers. Their contents, including creatine kinase
    and myoglobin, leak into the blood, producing rhabdomyolysis.
  biological_scale: TISSUE
  conforms_to: "sarcolemmal_fragility_myofiber_necrosis#Myofiber Necrosis"
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:38159459
    reference_title: "Novel OBSCN variants associated with a risk to exercise-intolerance and rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obscurin-deficient muscle fibers seem to have increased susceptibility
      to damage triggered by exercise that may lead to rhabdomyolysis.
    explanation: >-
      The authors' reading of their two patients: exercise damages
      obscurin-deficient fibers.
  downstream:
  - target: Exercise-induced rhabdomyolysis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40186404
      reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Deficiency of obscurin increases the risk of rhabdomyolysis by making
        muscle fibers more sensitive to exercise‐induced injury and decreasing
        membrane stability
      explanation: >-
        Links exercise-induced fiber injury to rhabdomyolysis. The sentence
        summarizes earlier work rather than this case report's own data.
  - target: Elevated circulating creatine kinase activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40186404
      reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinically, the patient presented with exercise-induced rhabdomyolysis
        accompanied by significant serum creatine kinase elevation
      explanation: >-
        Fiber breakdown releases creatine kinase into serum.
  - target: Myoglobinuria
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38159459
      reference_title: "Novel OBSCN variants associated with a risk to exercise-intolerance and rhabdomyolysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we reported two young patients with a history of cramps,
        myalgia, exercise intolerance, rhabdomyolysis, and myoglobinuria
      explanation: >-
        Myoglobin released from damaged fibers appears in the urine.
  - target: Exercise-induced myalgia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40186404
      reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Loss‐of‐function variants of OBSCN have been shown to cause
        exercise‐induced rhabdomyolysis (Cabrera‐Serrano et al. 2021;
        Zemorshidi et al. 2024), such as myalgia, cramps, and significant
        elevations in serum CK.
      explanation: >-
        Myalgia is named among the manifestations of the exercise-induced
        fiber breakdown.
phenotypes:
- name: Exercise-induced rhabdomyolysis
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Recurrent, often severe rhabdomyolysis triggered mainly by high-intensity
    exercise, with onset usually in childhood or the teenage years. One
    reported patient with biallelic variants had cramps and myalgia without
    rhabdomyolysis.
  phenotype_term:
    preferred_term: Exercise-induced rhabdomyolysis
    term:
      id: HP:0009045
      label: Exercise-induced rhabdomyolysis
    onset:
      onset_category: JUVENILE
      notes: >-
        Onset usually in the teenage years (PMID:34957489). The reported
        patients were 11 to 39 years old.
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present six patients who presented with severe and recurrent
      rhabdomyolysis, usually with onset in the teenage years
    explanation: >-
      Recurrent rhabdomyolysis is the defining feature of the founding
      series.
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main feature for these patients was childhood or adolescent onset,
      with exercise‐ or heat‐induced rhabdomyolysis
    explanation: >-
      Summary of the nine patients reported to date.
- name: Exercise-induced myalgia
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: >-
    Muscle pain after exertion, reported in eight of nine patients
    summarized in PMID:40186404, and the presenting symptom in patients
    without frank rhabdomyolysis.
  phenotype_term:
    preferred_term: Exercise-induced myalgia
    term:
      id: HP:0003738
      label: Exercise-induced myalgia
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accompanied by exercise intolerance (7/9) and myalgia (8/9)
    explanation: >-
      Myalgia in eight of nine reported patients.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a 22‐year‐old woman who experienced muscle stiffness, myalgia
      and cramps in her thighs and gluteal muscles after performing
      high‐intensity sports (roundnet).
    explanation: >-
      Exercise-induced myalgia in a patient with biallelic variants.
- name: Exercise-induced muscle cramps
  category: Musculoskeletal
  description: >-
    Cramps after exertion, in three of nine patients summarized in
    PMID:40186404 and in later reports.
  phenotype_term:
    preferred_term: Exercise-induced muscle cramps
    term:
      id: HP:0003710
      label: Exercise-induced muscle cramps
  evidence:
  - reference: PMID:34957489
    reference_title: "Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other features included a history of myalgia and muscle cramps
    explanation: >-
      Cramps are part of the phenotype in the founding series.
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients harbouring biallelic OBSCN nonsense variants can also present
      with exercise‐induced cramps and myalgia, as observed in our patient
      without developing the full clinical picture of rhabdomyolysis
    explanation: >-
      Exercise-induced cramps, sometimes without rhabdomyolysis.
- name: Exercise intolerance
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Reduced tolerance of strenuous exercise, in seven of nine patients
    summarized in PMID:40186404.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accompanied by exercise intolerance (7/9) and myalgia (8/9)
    explanation: >-
      Exercise intolerance in seven of nine reported patients.
- name: Elevated circulating creatine kinase activity
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >-
    Very high serum creatine kinase during episodes, with a reported mean
    over 275,000 IU/L and a maximum of 603,000 IU/L. Creatine kinase can
    stay raised for days after symptoms improve.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with significant elevation of serum CK (mean
      value over 275,000 IU/L and maximum up to 603,000 IU/L)
    explanation: >-
      Marked creatine kinase elevation in all nine reported patients.
- name: Myoglobinuria
  category: Renal
  description: >-
    Myoglobin in the urine during rhabdomyolysis episodes.
  phenotype_term:
    preferred_term: Myoglobinuria
    term:
      id: HP:0002913
      label: Myoglobinuria
  evidence:
  - reference: PMID:38159459
    reference_title: "Novel OBSCN variants associated with a risk to exercise-intolerance and rhabdomyolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we reported two young patients with a history of cramps, myalgia,
      exercise intolerance, rhabdomyolysis, and myoglobinuria
    explanation: >-
      Myoglobinuria in both patients of this report.
- name: Acute kidney injury
  category: Renal
  frequency: FREQUENT
  description: >-
    Renal failure complicating rhabdomyolysis, in three of nine reported
    patients.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal failure occurred in 3 patients (3/9), but cardiac function was
      normal in all patients.
    explanation: >-
      Kidney injury in a third of reported patients; no cardiac involvement.
- name: Increased variability in muscle fiber diameter
  category: Musculoskeletal
  description: >-
    Muscle biopsy findings are variable: fiber-size variation, internal
    nuclei, type 2 fiber predominance, ring and necrotic fibers, and
    core-like lesions.
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Previous studies of OBSCN‐associated myopathy revealed variable muscle
      pathology, including increased variation in muscle fibre size,
      internalised nuclei, ring fibres, necrotic fibres, predominance of type
      2 muscle fibres and core‐like pathology
    explanation: >-
      Summarizes biopsy findings across earlier reports.
environmental:
- name: Strenuous exercise
  description: >-
    High-intensity exercise is the main trigger of rhabdomyolysis episodes.
    Fever and heat are less common triggers.
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  evidence:
  - reference: PMID:41645489
    reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms are mainly induced by high-intensity sports.
    explanation: >-
      High-intensity exercise triggers symptoms.
  influences_mechanisms:
  - target: Exercise-Induced Myofiber Breakdown
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Intense exercise precipitates fiber breakdown in obscurin-deficient
      muscle.
    evidence:
    - reference: PMID:41645489
      reference_title: "Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the majority of these patients, cramps, myalgia and rhabdomyolysis
        were triggered by high‐intensity sports
      explanation: >-
        Exercise triggers the episodes in most reported patients.
diagnosis:
- name: Exome sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Reported cases were found by exome or panel sequencing of patients with
    recurrent rhabdomyolysis.
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole exome sequencing on a patient with exercise-induced
      rhabdomyolysis to identify possible causative gene variants.
    explanation: >-
      Diagnosis by exome sequencing.
treatments:
- name: Fluid therapy during acute rhabdomyolysis
  description: >-
    There is no OBSCN-directed therapy. Acute episodes are treated as for
    other causes of rhabdomyolysis, with intravenous fluids and urine
    alkalinization to protect the kidneys.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Fluid Therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_phenotypes:
  - preferred_term: Exercise-induced rhabdomyolysis
    term:
      id: HP:0009045
      label: Exercise-induced rhabdomyolysis
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient received routine pediatric care, including urine
      alkalinization, fluid replacement, and antioxidant therapy with vitamin
      C. Her symptoms significantly improved after five days of treatment
    explanation: >-
      Supportive fluid treatment of an acute episode, in one patient.
- name: Avoidance of strenuous exercise
  description: >-
    Patients are advised to avoid strenuous physical activity, the main
    trigger of episodes. No controlled study of this has been reported.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Exercise Counseling
    term:
      id: NCIT:C101235
      label: Exercise Counseling
  evidence:
  - reference: PMID:40186404
    reference_title: "Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      given the persistently high CK levels, she was advised to avoid
      strenuous physical activity
    explanation: >-
      Trigger avoidance was advised in this case.
animal_models:
- name: Obscurin knockout mouse
  species: Mouse
  genotype: Obscn-/-
  publication: PMID:23420875
  description: >-
    Obscn-null mice have a disorganized longitudinal sarcoplasmic reticulum,
    mislocalized ankyrin-B and dystrophin, sarcolemmal fragility, reduced
    running endurance and exercise-induced muscle damage, worst in the
    diaphragm and with age.
  modeled_mechanisms:
  - target: Sarcolemmal Fragility
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The knockout shows the membrane fragility and exercise intolerance
      proposed to underlie the human disease.
    limitations: >-
      Frank rhabdomyolysis with myoglobinuria has not been reported in the
      mouse. Exercise injury is most marked in the diaphragm, not the limb
      muscles affected in patients.
    evidence:
    - reference: PMID:23420875
      reference_title: "Obscurin is required for ankyrinB-dependent dystrophin localization and sarcolemma integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        these mutant mice displayed marked sarcolemmal fragility and reduced
        muscle exercise tolerance
      explanation: >-
        The knockout reproduces the fragility node.
  - target: Exercise-Induced Sarcomeric M-Band Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Seen in the diaphragm but not the hindlimb muscles of exercised mice.
    evidence:
    - reference: PMID:27784675
      reference_title: "Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        electron microscopy revealed that, in the diaphragm of exercised
        obscurin KO mice, but not in the hindlimb muscles, both M-line and
        H-zone of sarcomeres appeared wavy and less defined
      explanation: >-
        M-band disorganization after exercise, limited to the diaphragm.
discussions:
- discussion_id: rhabdo1_mouse_model_mismatch
  prompt: >-
    Why does obscurin loss cause trigger-dependent recurrent rhabdomyolysis
    in people, when obscurin-knockout mice show at most mild, mainly
    diaphragmatic exercise injury and no frank rhabdomyolysis?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Sarcolemmal Fragility
  - pathophysiology#Exercise-Induced Myofiber Breakdown
  - animal_models#Obscurin knockout mouse
  rationale: >-
    The membrane and sarcoplasmic reticulum defects proposed for the human
    disease come mainly from mice, where the paralog Obsl1 compensates for
    obscurin loss and the single knockout is mild. The only human functional
    readout is reduced sarcoplasmic reticulum calcium in starved patient
    myoblasts. Whether OBSL1 compensates less in human skeletal muscle, or
    the human trigger load is simply larger, is untested.
  evidence:
  - reference: PMID:31098411
    reference_title: "Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar
      to obscurin knockouts
    explanation: >-
      Single obscurin knockout mice are mild, unlike the human disease.
📚

References & Deep Research

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)

Review round 1: Rhabdomyolysis Susceptibility To 1 · 2026-10-27T18:54:24Z · View source

Addressed optional review suggestions on PR 15754. Replaced the snippet on the Exercise-Induced Myofiber Breakdown to Exercise-induced myalgia edge, which named the triggers but not myalgia, with the PMID:40186404 sentence listing myalgia among the manifestations. Added genetic evidence from PMID:40813169 (a further patient with two OBSCN variants) and PMID:33438037 (two cardiomyopathy-associated missense variants left titin binding and stability unchanged), both previously named only in notes. PMID:33438037 is graded NO_EVIDENCE, since it supports the missense caution rather than the loss-of-function claim of the record. Did not add further variants, since the founding-series alleles are listed only in the deep-research report and not in the cached abstracts, and did not add a fever environmental entry, since ECTO has no fever exposure in the term cache and fever is a host state rather than an exposure. Snippets 48/48 verified.

Create: Rhabdomyolysis Susceptibility To 1 (OBSCN, MONDO:0859371) · 2026-10-27T18:30:42Z · View source

New entry for autosomal recessive OBSCN loss-of-function rhabdomyolysis susceptibility (RHABDO1, OMIM:620235). Literature was gathered from PubMed (the founding Brain 2022 series, four later case reports, and the obscurin-knockout mouse studies), and an OpenScientist deep-research report was run and screened with just preflight-dr. Preflight confirmed the entity but flagged that the report labels OBSCN as HGNC:16542, which is PPIAP2; the entry binds hgnc:15719 from the term cache instead. From the report, the Obscn/Obsl1 double-knockout study (PMID:31098411) and the obscurin missense caution (PMID:33438037) were added; the report's HPO annotations without a citable source (distal weakness, acylcarnitine abnormality) and its unsourced fasting trigger were not taken. The pathograph runs from obscurin loss through sarcoplasmic reticulum disorganization, sarcolemmal fragility and exercise-induced M-band disorganization to myofiber breakdown, conforming to the sarcolemmal_fragility_myofiber_necrosis module at its fragility and necrosis nodes. A HUMAN_MODEL_MISMATCH discussion records that knockout mice do not develop rhabdomyolysis. Validated with just validate, validate-terms, count-verified-snippets (46/46), and the offline KB gates.

OpenScientist ▸
Rhabdomyolysis, Susceptibility To, 1 (RHABDO1) — Comprehensive Disease Report
openscientist-autonomous 25 citations 2026-10-27T18:22:33.322263

Rhabdomyolysis, Susceptibility To, 1 (RHABDO1) — Comprehensive Disease Report

Disease: Rhabdomyolysis, Susceptibility To, 1 (RHABDO1) MONDO ID: MONDO:0859371 · OMIM: 620235 · Causal gene: OBSCN (obscurin; HGNC:16542; UniProt Q5VST9; chromosome 1q42) Category: Mendelian (autosomal recessive)

Gene identity (stated up front): The causal gene for Rhabdomyolysis Susceptibility To 1 is OBSCN, which encodes obscurin, a giant (~800 kDa) sarcomeric cytoskeletal/signaling protein. This report concerns the OBSCN-related entity (OMIM 620235), not rhabdomyolysis caused by other genes (e.g., RYR1, LPIN1, CPT2, PYGM, ANO5, fatty-acid-oxidation genes).

Summary

Rhabdomyolysis, Susceptibility To, 1 (RHABDO1) is a rare Mendelian skeletal-muscle disorder caused by bi-allelic loss-of-function (LOF) variants in OBSCN, the gene encoding obscurin — a giant (~800 kDa) modular sarcomeric signaling and structural protein that physically links the contractile sarcomere (at the M-band and Z-disk) to the sarcoplasmic reticulum (SR). The disease was defined by Cabrera-Serrano and colleagues (Brain, 2022), who identified 10 bi-allelic LOF OBSCN variants in six unrelated patients with severe, recurrent exertional rhabdomyolysis and demonstrated reduced OBSCN expression and loss of obscurin protein in patient muscle (PMID: 34957489). This case series established OMIM 620235.

The core clinical picture is teenage-onset, recurrent, severe rhabdomyolysis precipitated by metabolic or mechanical triggers (strenuous exercise, fasting, febrile illness), accompanied by myalgia, muscle cramps, exercise intolerance, markedly elevated serum creatine kinase (CK), and myoglobinuria that risks acute kidney injury (AKI). A distinguishing feature is cardiac sparing — despite prior literature linking OBSCN to cardiomyopathy, RHABDO1 patients consistently lack cardiomyopathy and have normal cardiac examinations. The mechanistic model, supported by patient myoblast studies and mouse Obscn/Obsl1 models, is that obscurin loss disorganizes the SR and impairs Ca²⁺ re-uptake/storage, sensitizing myofibers to metabolic and mechanical stress and precipitating episodic myofiber breakdown.

Genetically, OBSCN is not constrained against heterozygous LOF in gnomAD (pLI ≈ 0, LOEUF ≈ 0.94), consistent with recessive inheritance in which a single LOF allele is tolerated. In ClinVar, truncating OBSCN variants (nonsense/frameshift) associated with rhabdomyolysis are classified Pathogenic/Likely-pathogenic, whereas missense variants are predominantly Variants of Uncertain Significance (VUS). There is no gene-specific therapy; management is supportive (aggressive IV fluid resuscitation, electrolyte and renal monitoring during crises) combined with trigger avoidance and genetic counseling. This report synthesizes evidence across the defining human case series, three additional case reports, gnomAD constraint data, ClinVar classifications, UniProt domain architecture, Monarch/HPO phenotype annotations, and mouse models.

Section 1 — Disease Information

Overview. RHABDO1 is an autosomal-recessive susceptibility to recurrent rhabdomyolysis — acute skeletal-muscle fiber breakdown with release of intracellular contents (CK, myoglobin, electrolytes) into the circulation. Affected individuals are often asymptomatic or only mildly symptomatic between episodes but develop severe crises when exposed to triggers. The condition is a genetic susceptibility rather than a continuously progressive myopathy: episodes are trigger-dependent and episodic, with normal or near-normal muscle strength between attacks in most patients.

Key identifiers.

Resource Identifier
OMIM 620235 (Rhabdomyolysis, susceptibility to, 1)
MONDO MONDO:0859371
Causal gene OBSCN (HGNC:16542; NCBI Gene; Ensembl ENSG00000154358)
Protein Obscurin, UniProt Q5VST9
Cytoband 1q42
Orphanet / ICD-10 / ICD-11 / MeSH No dedicated RHABDO1-specific code identified; rhabdomyolysis maps to ICD-10 M62.82 and MeSH D012206 (Rhabdomyolysis)

Synonyms / alternative names. No formal synonyms are recorded in the template. The condition is referred to descriptively in the literature as "OBSCN-related rhabdomyolysis," "obscurin-deficiency rhabdomyolysis," and "bi-allelic OBSCN loss-of-function rhabdomyolysis."

Information source. The knowledge base here is derived from aggregated disease-level resources (OMIM, ClinVar, gnomAD, HPO/Monarch, UniProt) and individual patient case reports/series in the primary literature — not from a large EHR cohort. The total reported patient count worldwide is small (roughly a dozen across the defining series and subsequent case reports).

Section 2 — Etiology

Disease causal factors. The primary cause is genetic: bi-allelic (homozygous or compound-heterozygous) loss-of-function variants in OBSCN. The defining study identified 10 bi-allelic LOF OBSCN variants across six unrelated patients (PMID: 34957489). Disease expression, however, is gene–environment dependent: the genetic lesion establishes susceptibility, while an environmental/metabolic trigger (exertion, fasting, fever/infection) precipitates each acute episode.

Genetic risk factors. The causal variants are LOF alleles in OBSCN (nonsense, frameshift, canonical splice-site). Because OBSCN tolerates heterozygous LOF (gnomAD pLI ≈ 0), two defective alleles are required for disease. No established modifier genes are proven for RHABDO1 specifically, though the paralogue OBSL1 (obscurin-like 1) provides functional redundancy in muscle (relevant to mechanism; see Section 6).

Environmental risk factors / triggers. Based on the clinical descriptions: strenuous or unaccustomed exercise, fasting/caloric deprivation, febrile illness/infection, and likely dehydration and heat stress (the classic precipitants of exertional rhabdomyolysis generally). Patient myoblasts were shown to be more susceptible to starvation specifically (PMID: 34957489), providing a direct link between a metabolic trigger and cellular vulnerability.

Protective factors. No validated genetic protective variants or protective alleles are reported. By inference, avoidance of triggers (adequate hydration, avoiding prolonged fasting, graded rather than sudden intense exercise, prompt management of febrile illness) is protective against episodes. No nutritional or pharmacologic protective factor has been established.

Gene–environment interactions. RHABDO1 is a prototypical gene × environment disorder: the OBSCN LOF genotype lowers the threshold at which metabolic/mechanical stress triggers Ca²⁺ dysregulation and myofiber breakdown. The starvation-sensitivity of patient myoblasts is the best-characterized GxE link (PMID: 34957489).

Section 3 — Phenotypes

The official Monarch/HPO disease–phenotype annotation set for MONDO:0859371 comprises 10 terms, spanning episodic clinical features, laboratory abnormalities, and muscle-biopsy histopathology.

Phenotype HPO term Type Notes
Elevated circulating creatine kinase HP:0003236 Laboratory abnormality Markedly elevated during episodes (CK can reach hundreds of thousands U/L in rhabdomyolysis)
Rhabdomyolysis HP:0003201 Clinical sign Core defining feature; recurrent/episodic
Myalgia HP:0003326 Symptom Muscle pain, often with cramps
Exercise intolerance HP:0003546 Symptom Common trigger-associated complaint
Renal insufficiency HP:0000083 Laboratory/clinical Secondary to myoglobinuria (AKI risk)
Increased variability in muscle fiber diameter HP:0003557 Histopathology Muscle-biopsy finding
Centrally nucleated skeletal muscle fibers HP:0003687 Histopathology Muscle-biopsy finding
Type 2 muscle fiber predominance HP:0010602 Histopathology Muscle-biopsy finding
Distal muscle weakness HP:0002460 Clinical sign Variable; not universal
Abnormal circulating fatty acylcarnitine concentration HP:0012071 Laboratory abnormality Metabolic workup finding

Phenotype characteristics. - Age of onset: typically teenage years (adolescence), as described in the defining series — "usually with onset in the teenage years" (PMID: 34957489). Subsequent reports describe young adults/young patients. - Severity: severe and recurrent episodes of rhabdomyolysis; variable between episodes and between individuals (variable expressivity). - Progression: episodic/relapsing, trigger-dependent; not a steadily progressive degenerative myopathy. Patients are often well between episodes. - Frequency among affected individuals: myalgia, muscle cramps, exercise intolerance and elevated CK are consistent features; cardiomyopathy is characteristically absent.

Cardiac sparing. Multiple reports emphasize no cardiomyopathy: the defining series found no cardiomyopathy despite prior OBSCN–cardiomyopathy associations and normal cardiac exams (PMID: 34957489); Zemorshidi et al. described two young patients "without any evidence of concomitant cardiomyopathy" (PMID: 38159459); Sun et al. reported edema on MRI "without significant muscle weakness or cardiac abnormalities" (PMID: 40186404).

Quality-of-life impact. No disease-specific EQ-5D/SF-36/PROMIS data exist for RHABDO1. By inference, QoL impact derives from recurrent painful episodes, hospitalizations for crises, exercise limitation, and anxiety about triggers; between episodes, function is often preserved.

Section 4 — Genetic / Molecular Information

Causal gene. OBSCN (obscurin), HGNC:16542, chromosome 1q42; Ensembl ENSG00000154358. OBSCN has 121 non-overlapping exons and encodes some of the largest known mRNAs in the human genome, undergoing extensive developmentally- and tissue-regulated alternative splicing (PMID: 40025502). The same gene underlies both a cardiomyopathy disease axis and the rhabdomyolysis axis, with isoform- and domain-specific effects.

Pathogenic variants (RHABDO1-associated). Pathogenic/likely-pathogenic variants are loss-of-function (nonsense, frameshift, canonical splice). Representative ClinVar entries (transcript NM_001386125.1), classified Pathogenic (P) or Likely-pathogenic (LP):

cDNA Protein Type ClinVar class
c.20788C>T p.Gln6930Ter Nonsense Pathogenic
c.7485_7486insCCCGCCC p.Thr2496fs Frameshift Pathogenic
c.5943C>A p.Cys1981Ter Nonsense Likely pathogenic
c.25879_25880del p.Lys8627fs Frameshift Likely pathogenic
c.20292C>G p.Tyr6764Ter Nonsense Likely pathogenic
c.23841dup p.Gly7948fs Frameshift Likely pathogenic
c.19607C>A p.Ser6536Ter Nonsense Likely pathogenic
c.15307C>T p.Gln5103Ter Nonsense Likely pathogenic
c.12859C>T p.Gln4287Ter Nonsense Likely pathogenic

Additional genotypes from case reports: compound heterozygous c.21184C>T (nonsense) + c.15610+12C>T (intronic splicing; absent from gnomAD_EAS) (PMID: 40186404); novel variants c.24822C>A and c.2653+1G>C (PMID: 38159459); and c.20292C>A + c.708del (PMID: 40813169).

Variant classification caveat. Missense, synonymous, and splice-region changes in the same rhabdomyolysis-annotated ClinVar set are largely VUS (e.g., p.Arg7149Pro, p.Val6753Leu, p.Trp1659Cys). This is reinforced by functional work showing that two cardiomyopathy-associated obscurin missense variants (R4344Q, R4444W) did not alter titin binding or domain thermostability and that R4344Q is present in 15% of African Americans, arguing against pathogenicity — a cautionary tale for over-calling OBSCN missense variants (PMID: 33438037). OBSCN has ~150 total P/LP ClinVar entries across all phenotypes.

Allele frequency / population constraint. gnomAD v2.1.1 constraint for OBSCN: pLI = 7.4×10⁻²²⁶ (≈ 0), observed/expected LOF (oe_lof) = 0.88 (90% CI 0.83–0.94; LOEUF 0.94), with 768 observed vs 870.9 expected LOF alleles; missense constraint low (mis_z = 0.53, oe_mis = 0.99). Interpretation: OBSCN is not depleted of heterozygous LOF variants, consistent with recessive inheritance where carriers are unaffected.

Somatic vs germline. All reported variants are germline. No somatic involvement is relevant to this disorder.

Functional consequences. Loss of function — reduced OBSCN expression and loss of obscurin protein in patient muscle (PMID: 34957489). This contrasts with proposed gain-of-function/dominant-negative mechanisms sometimes invoked for OBSCN cardiomyopathy variants.

Modifier genes / epigenetics / chromosomal abnormalities. No established modifier genes, epigenetic marks, or large-scale chromosomal abnormalities are described specifically for RHABDO1. OBSL1 redundancy is mechanistically relevant (Section 6). Alternative splicing of OBSCN may be regulated in part by BUB3 (PMID: 40025502).

Section 5 — Environmental Information

Environmental / triggering factors. The disease requires an environmental trigger to produce episodes. Established/implicated precipitants: strenuous or unaccustomed physical exertion, fasting/starvation, febrile illness, and plausibly dehydration and heat. Patient myoblasts are specifically more susceptible to starvation (PMID: 34957489).

Lifestyle factors. Exercise intensity and pattern, hydration status, and fasting behavior modulate risk. There is no reported association with smoking, alcohol, or diet beyond the fasting trigger.

Infectious agents. No pathogen causes RHABDO1. However, febrile infections act as triggers of acute episodes — a general feature of metabolic/genetic rhabdomyolysis susceptibilities. (For context, infections such as SARS-CoV-2 can independently cause rhabdomyolysis, PMID: 34871534, but this is etiologically distinct from the OBSCN genetic susceptibility.)

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

  1. Bi-allelic LOF variant in OBSCN (nonsense/frameshift/splice) → loss of obscurin protein in skeletal myofibers (demonstrated: reduced OBSCN expression and absent obscurin in patient muscle, PMID: 34957489).
  2. Loss of obscurin removes the structural/signaling link between the sarcomere (M-band/Z-disk) and the SR → disorganization of the SR and loss of normal SR architecture (demonstrated in mouse models; inferred in human: combined loss of Obscn/Obsl1 disrupts SR organization, PMID: 31098411).
  3. SR disorganization + reduced SERCA/phospholamban expression → impaired Ca²⁺ re-uptake and reduced SR Ca²⁺ storage → perturbed Ca²⁺ cycling (demonstrated in mouse: reduced SR volume, lower SERCA/PLB, altered Ca²⁺ cycling, PMID: 40366302, PMID: 40066567).
  4. Under a metabolic/mechanical trigger (exercise, fasting, fever) → myofibers with compromised Ca²⁺ handling cannot buffer the additional stress; patient myoblasts show a greater drop in SR Ca²⁺ content upon starvation than controls (demonstrated, PMID: 34957489).
  5. Dysregulated cytosolic Ca²⁺ and sarcolemmal instability → activation of Ca²⁺-dependent proteases/phospholipases and loss of membrane integrity → myofiber necrosis / rhabdomyolysis (inferred mechanism; sarcolemmal instability demonstrated in Obscn/Obsl1 double-KO mouse, PMID: 31098411).
  6. Myofiber breakdown → release of CK and myoglobin → markedly elevated serum CK, myoglobinuria → acute kidney injury when severe (clinical observation, PMID: 34957489, PMID: 40186404).

Branch (cardiac, largely spared in RHABDO1): In the heart, obscurin loss produces a separate disease axis — reduced SR volume with preserved T-tubules, lower SERCA/PLB, dilated cardiomyopathy and arrhythmia susceptibility in mice (PMID: 40366302); domain-specific Ig58/59 deletion causes atrial remodeling and Ca²⁺-based arrhythmogenesis (PMID: 39804820). In human RHABDO1, however, the cardiac axis is not manifest (cardiac sparing), likely reflecting isoform/redundancy differences between skeletal and cardiac muscle.

Supporting molecular detail

Protein architecture (UniProt Q5VST9, canonical 7,968 aa). Obscurin contains ~55 Ig-like domains, 4 fibronectin type-III (Fn3) domains, a calmodulin-binding IQ motif (aa 4872–4901), a tandem SH3 (5600–5667)–DH (5693–5877)–PH (5895–6004) RhoGEF signaling module, and two C-terminal Ser/Thr protein kinase domains (PK1 6468–6721; PK2 7672–7924). The N-terminal Ig1–3 domains target obscurin to the M-band/Z-disk via interactions with titin and myomesin.

Sarcomere–SR linkage. Obscurin's N-terminus binds M-band titin and myomesin; downregulation of myomesin disrupts obscurin M-band integration (PMID: 18477606). Crystallographic work defines the titin M10–obsl1/obscurin Ig–Ig interface and shows that disease-linked titin M10 mutations disrupt this complex (PMID: 20133654). Obscurin's C-terminus binds the N-terminal Z-disk region of titin and coassembles during myofibrillogenesis; the protein carries IQ (Ca²⁺/calmodulin) and RhoGEF (G-protein) signaling modules (PMID: 11448995). The RhoGEF domain selectively activates RhoA at the M-band in skeletal muscle and responds to lengthening-contraction injury (PMID: 19605563).

Functional redundancy with OBSL1. Single deletion of obscurin or Obsl1 is tolerated in mouse muscle; only combined deletion reveals roles in sarcolemmal stability and SR organization (PMID: 31098411). This redundancy may explain variable expressivity and the relatively mild baseline state between episodes.

Metabolic / mitochondrial dimension. Combined Obsc/Obsl1 loss in heart altered metabolism, reduced Chchd3 (a MICOS complex protein), produced abnormal mitophagy and increased unfolded protein response (PMID: 40066567). The abnormal acylcarnitine finding (HP:0012071) and starvation-sensitivity in human myoblasts point to an energy-metabolism vulnerability that intersects with Ca²⁺ handling.

Ontology suggestions. - GO biological process: regulation of release of sequestered calcium ion into cytosol (GO:0051279); sarcomere organization (GO:0045214); muscle contraction (GO:0006936); Rho protein signal transduction (GO:0007266); striated muscle cell development (GO:0055002). - GO cellular component: sarcoplasmic reticulum (GO:0016529); M band (GO:0031430); Z disc (GO:0030018); sarcomere (GO:0030017); sarcolemma (GO:0042383). - Cell types (CL): skeletal muscle fiber / myofiber (CL:0000188); fast muscle cell / type II fiber (CL:0000190). - CHEBI: calcium(2+) (CHEBI:29108); creatine (CHEBI:16919); creatinine (CHEBI:16737).

Section 7 — Anatomical Structures Affected

Organ level. Primary: skeletal muscle (striated muscle; UBERON:0001134). Secondary: kidney (UBERON:0002113) via myoglobinuric acute kidney injury. Body system: musculoskeletal/muscular system primarily; renal/urinary system secondarily. The heart (myocardium, UBERON:0002349) is characteristically spared in RHABDO1.

Tissue and cell level. Affected tissue: skeletal muscle tissue (UBERON:0002036); affected cells: skeletal muscle fibers/myofibers (CL:0000188), with type 2 fiber predominance (HP:0010602) on biopsy. Histopathology shows increased fiber-size variability (HP:0003557) and centrally nucleated fibers (HP:0003687).

Subcellular level. Sarcoplasmic reticulum (GO:0016529) — the key disorganized compartment; M-band (GO:0031430) and Z-disk (GO:0030018) where obscurin localizes; sarcolemma (GO:0042383) instability; mitochondria (GO:0005739) secondarily implicated via metabolic/mitophagy changes in models.

Localization / lateralization. Skeletal muscle involvement is generalized/bilateral; imaging in one case showed bilateral lower-limb muscle edema on MRI (PMID: 40186404).

Section 8 — Temporal Development

Onset. Typically adolescence (teenage years) per the defining series (PMID: 34957489); additional cases are young adults. Onset of individual episodes is acute, tied to a trigger.

Progression. The disease course is episodic/relapsing rather than steadily progressive. Between episodes, patients are frequently well, though some show distal muscle weakness (HP:0002460) and biopsy changes. Individual rhabdomyolysis episodes evolve acutely (hours), with CK rising rapidly and resolving over days with supportive care.

Patterns. Episodes remit with trigger removal and supportive treatment. The critical window for intervention is during an acute crisis (early aggressive hydration to prevent AKI). Lifelong susceptibility persists; management is about preventing recurrence.

Expressivity. Variable: Sun et al. noted the proband's mother, carrying a homozygous OBSCN variant, had only exercise-induced myalgia, far milder than the proband's rhabdomyolysis — illustrating variable expressivity (PMID: 40186404).

Section 9 — Inheritance and Population

Inheritance pattern. Autosomal recessive — bi-allelic (homozygous or compound-heterozygous) LOF variants required (PMID: 34957489). Supported by gnomAD constraint showing OBSCN tolerates heterozygous LOF (pLI ≈ 0, LOEUF 0.94), so carriers are generally unaffected.

Penetrance / expressivity. Appears trigger-dependent with variable expressivity (e.g., homozygous carrier mother with only myalgia, PMID: 40186404). Penetrance is incompletely defined due to the small number of reported cases.

Epidemiology. Prevalence and incidence are not established — RHABDO1 is a recently defined (2022), rare Mendelian condition with only ~12 reported patients across the literature. No registry-level prevalence/incidence figures exist.

Founder effects / consanguinity / carrier frequency. No founder mutation is established. Consanguinity may facilitate homozygous cases but is not systematically reported. Carrier frequency cannot be reliably estimated but LOF alleles are observed in gnomAD.

Population demographics. No ethnic predilection is established. Cases are reported from multiple populations (including East Asian cases, PMID: 40186404). Sex ratio is not established; reported cases include males and females. Age distribution skews to adolescents/young adults at first presentation.

Section 10 — Diagnostics

Laboratory tests. During episodes: markedly elevated serum CK (HP:0003236), myoglobinuria, and renal function monitoring for AKI (HP:0000083). Metabolic workup may show abnormal fatty acylcarnitine profile (HP:0012071) — important because acylcarnitine abnormalities also characterize the key differential (fatty-acid oxidation disorders).

Biomarkers. CK and myoglobin are the principal circulating biomarkers of myofiber breakdown; absent/reduced obscurin on muscle immunostaining/Western blot is a disease-specific tissue marker (PMID: 34957489).

Imaging. Muscle MRI can show muscle edema (bilateral lower-limb edema reported, PMID: 40186404).

Biopsy / histopathology. Muscle biopsy may show increased fiber-size variability (HP:0003557), centrally nucleated fibers (HP:0003687), type 2 fiber predominance (HP:0010602), and reduced/absent obscurin by immunostaining.

Genetic testing (diagnostic cornerstone). Because OBSCN is enormous (121 exons, among the largest human transcripts, PMID: 40025502), next-generation sequencing (WES or WGS) is the practical approach; large multigene rhabdomyolysis/metabolic-myopathy panels that include OBSCN are appropriate. Confirm bi-allelic status and phase (compound-het vs in-cis) with parental testing. Interpret truncating variants as likely causal; treat missense as VUS pending functional/segregation data (PMID: 33438037).

Clinical criteria. No formal consensus diagnostic criteria exist. Working diagnosis = recurrent exertional/metabolic rhabdomyolysis + bi-allelic LOF OBSCN variants + supportive muscle findings (reduced obscurin), after exclusion of commoner causes.

Differential diagnosis. Other genetic rhabdomyolysis susceptibilities and metabolic myopathies must be excluded:

Differential Gene / defect Distinguishing feature
RYR1-related / malignant hyperthermia susceptibility RYR1 Anesthetic-triggered MH; RYR1 variants (PMID: 35285867)
VLCAD deficiency (FAO disorder) ACADVL Abnormal acylcarnitines; fasting/exercise triggers (PMID: 35405752, PMID: 29153022)
McArdle disease (GSD V) PYGM Second-wind phenomenon; fixed exercise intolerance (PMID: 41229646)
Drug-induced rhabdomyolysis statins, TKIs Temporal drug association (PMID: 42473504, PMID: 41585502)
Infection-triggered e.g., SARS-CoV-2 Acute infection context (PMID: 34871534)
Exertional / MH-spectrum multifactorial Round-table consensus on ER/EHS/MH overlap (PMID: 28430550)

Screening. No newborn or population screening exists. Cascade genetic testing of relatives of probands is reasonable for recurrence risk and trigger-avoidance counseling.

Section 11 — Outcome / Prognosis

Survival / mortality. No disease-specific mortality data. Prognosis is generally good with prompt supportive management; the principal acute risk is myoglobinuric AKI (HP:0000083), which can require dialysis in severe rhabdomyolysis generally (PMID: 33645199). Rhabdomyolysis can occasionally be severe even without electrolyte abnormalities or renal failure (PMID: 42491205).

Morbidity / function. Between episodes, function is often preserved; recurrent crises, hospitalizations, and exercise restriction are the main morbidity. Some patients show distal weakness.

Complications. AKI (sometimes requiring dialysis), electrolyte derangements (hyperkalemia, hyperphosphatemia, hypocalcemia) during severe episodes, and rarely compartment syndrome (general rhabdomyolysis complications).

Recovery potential. Individual episodes typically recover fully with hydration and supportive care; CK normalizes over days.

Prognostic factors. Severity/number of triggers, rapidity of fluid resuscitation, baseline renal function, and degree of CK elevation influence AKI risk. No molecular prognostic biomarker specific to RHABDO1 is established.

Section 12 — Treatment

No gene-specific therapy exists. Management is supportive and preventive.

Acute episode management. Aggressive intravenous fluid resuscitation to maintain renal perfusion and clear myoglobin; electrolyte correction; renal function monitoring; dialysis if AKI is severe. This mirrors standard rhabdomyolysis care (PMID: 33645199). (NCIT intervention terms: Intravenous Fluid Therapy; Hemodialysis; Supportive Care.)

Preventive / supportive. Trigger avoidance — adequate hydration, avoiding prolonged fasting, graded conditioning rather than sudden intense/unaccustomed exertion, prompt management of febrile illness, and caution with heat. Individualized exercise-tolerance assessment (as applied in metabolic myopathies) may define safe activity limits.

Pharmacotherapy / advanced therapeutics. No approved pharmacologic, gene, cell, or RNA-based therapy is specific to RHABDO1. No pharmacogenomic guidance is established.

Treatment strategy. The practical algorithm: (1) recognize recurrent rhabdomyolysis; (2) rule out common causes; (3) genetic confirmation of bi-allelic OBSCN LOF; (4) acute supportive care during episodes; (5) long-term trigger-avoidance counseling and genetic counseling for the family.

Section 13 — Prevention

  • Primary prevention: Not applicable at population level (rare Mendelian disorder). For at-risk/affected individuals, trigger avoidance is the key primary preventive measure against episodes.
  • Secondary prevention: Early recognition of prodromal myalgia/dark urine and prompt hydration to abort/limit episodes and prevent AKI.
  • Tertiary prevention: Aggressive management during crises to prevent renal failure and complications.
  • Genetic counseling: Autosomal-recessive recurrence risk (25% for future sibs of a proband when both parents are carriers); cascade testing of relatives; reproductive counseling.
  • No immunization, public-health, or environmental program applies specifically.

Section 14 — Other Species / Natural Disease

  • Taxonomy / orthologues: Obscurin is conserved in mammals; mouse Obscn (NCBI Gene) and the paralogue Obsl1 are the principal experimental orthologues. The invertebrate analogue is UNC-89 (C. elegans), which, like obscurin, localizes to the M-band (PMID: 18477606).
  • Natural disease in animals: No naturally occurring OBSCN-rhabdomyolysis disease is documented in companion animals or wildlife. Exertional rhabdomyolysis is, however, a major condition in horses (sporadic and recurrent/chronic forms), with intrinsic genetic contributors in some equine syndromes — a comparative-biology parallel, though not OBSCN-specific (PMID: 39880734).
  • Evolutionary conservation: The sarcomere–SR linkage role of obscurin and its M-band targeting are conserved from invertebrates (UNC-89) to mammals, supporting cross-species mechanistic relevance.

Section 15 — Model Organisms

Model Type Key findings Relevance to RHABDO1 PMID
Obscn / Obsl1 double-KO mouse (skeletal) Mammalian KO Only combined deletion reveals roles in sarcolemmal stability and SR organization and muscle metabolism Strong mechanistic support for SR/sarcolemma defect; highlights OBSL1 redundancy 31098411
Obscn KO mouse (heart) Mammalian KO Reduced SR volume, lower SERCA/PLB, altered Ca²⁺ cycling, compensated dilated cardiomyopathy, arrhythmia Models the cardiac branch; informs Ca²⁺-handling mechanism 40366302
Obsc/Obsl1 double-KO (heart) Mammalian KO Diastolic dysfunction, perturbed Ca²⁺ cycling, altered metabolism, deregulated mitophagy, ↑UPR Links obscurin loss to SR + mitochondrial/metabolic dysfunction 40066567
Obscn-ΔIg58/59 mouse Knock-in/deletion Atrial remodeling, Ca²⁺-based arrhythmogenesis, TAT depletion Domain-specific cardiac model (distinct from skeletal rhabdo) 39804820
Patient-derived cultured myoblasts In vitro (human) Greater decrease in SR Ca²⁺ content upon starvation vs controls Direct human functional evidence of impaired SR Ca²⁺ handling 34957489

Phenotype recapitulation / limitations. Mouse models robustly recapitulate the SR disorganization and Ca²⁺-handling defect central to RHABDO1, but the cardiac phenotype dominates mouse models whereas human RHABDO1 spares the heart — a key species/isoform discrepancy. No mouse model has been reported that reproduces the human trigger-dependent recurrent skeletal rhabdomyolysis phenotype in isolation, partly because of OBSL1 redundancy. Human patient myoblasts provide the most disease-faithful functional readout to date. Model databases: MGI, IMPC, IMSR for murine resources.

Mechanistic Model / Interpretation

 Bi-allelic OBSCN LOF variant (nonsense / frameshift / splice)
    │  (demonstrated: reduced OBSCN, absent obscurin in patient muscle)
    ▼
 Loss of obscurin at M-band / Z-disk  --X--  (loses titin & myomesin linkage)
    │
    ▼
 Disrupted sarcomere->SR coupling -> SR disorganization
   + reduced SERCA / phospholamban (model evidence)
    │
    ▼
 Impaired Ca2+ re-uptake & reduced SR Ca2+ storage -> perturbed Ca2+ cycling
    │
    │<---- TRIGGER (exercise / fasting / fever)
    │       (patient myoblasts: lower SR Ca2+ on starvation)
    ▼
 Cytosolic Ca2+ dysregulation + sarcolemmal instability
    │
    ▼
 Myofiber necrosis (RHABDOMYOLYSIS)
    │
    ├─> ↑↑ serum CK, myalgia, cramps, exercise intolerance
    └─> Myoglobinuria -> Acute kidney injury (risk)

 BRANCH (heart): same SR/Ca2+ lesion -> dilated CM / arrhythmia in MICE
         but CARDIAC SPARING in human RHABDO1 (isoform/redundancy)

The unifying interpretation: RHABDO1 is a sarcoplasmic-reticulum Ca²⁺-handling disorder of skeletal muscle caused by obscurin loss of function. The upstream lesion is structural (loss of the sarcomere–SR tether); the downstream consequence is a Ca²⁺-buffering deficit that stays clinically silent until a metabolic or mechanical trigger overwhelms the compromised myofiber, producing episodic breakdown. Cardiac sparing in humans — despite a clear cardiac disease axis in mice and in OBSCN-cardiomyopathy literature — is the most striking unexplained feature and points to tissue-specific isoform usage and OBSL1 redundancy.

Evidence Base

PMID Study Role in this report
34957489 Cabrera-Serrano et al., Brain 2022 — defining case series Primary source: 10 bi-allelic LOF OBSCN variants in 6 patients; reduced OBSCN/absent obscurin; starvation-sensitive SR Ca²⁺ in myoblasts; cardiac sparing; teenage onset
38159459 Zemorshidi 2024 — case report Two young patients, novel variants, exercise intolerance/rhabdomyolysis without cardiomyopathy
40186404 Sun 2025 — case report Compound-het nonsense+splice; homozygous mother with milder phenotype (variable expressivity); MRI muscle edema, no cardiac abnormality
40813169 Liu 2025 — case report + review Young adult, two OBSCN variants; reinforces pathogenic role; notes mechanism unclear
31098411 Murine Obscn/Obsl1 — skeletal Only combined deletion reveals SR organization + sarcolemmal stability roles (mechanism)
40366302 Obscn KO heart Reduced SR volume, ↓SERCA/PLB, altered Ca²⁺ cycling (mechanism; cardiac branch)
40066567 Obsc/Obsl1 KO heart SR + mitochondrial/metabolic dysfunction, mitophagy (mechanism)
39804820 Obscn-ΔIg58/59 Atrial Ca²⁺ arrhythmogenesis (distinct cardiac axis)
18477606 Titin/myomesin–obscurin M-band Molecular basis of obscurin M-band targeting
20133654 Titin M10–obsl1 structure M-band complex structure; disease mutations disrupt it
11448995 Obscurin discovery ~800 kDa, 1q42, IQ + RhoGEF signaling, titin binding
19605563 Obscurin RhoGEF Activates RhoA at M-band; injury response
33438037 Obscurin missense variants Cautionary: R4344Q/R4444W not clearly pathogenic; supports VUS treatment of missense
40025502 OBSCN splicing 121 exons; extensive alternative splicing; cardiac vs skeletal isoforms
39880734 Equine exertional rhabdomyolysis Comparative biology context
33645199 Rhabdomyolysis→AKI Supportive-care/complication context

Limitations and Knowledge Gaps

  1. Very small patient numbers. RHABDO1 was defined in 2022; only ~12 patients are reported. Prevalence, incidence, penetrance, sex ratio, and natural history are therefore poorly quantified.
  2. Mechanism partly inferred from models. The SR-disorganization/Ca²⁺ steps rest heavily on mouse Obscn/Obsl1 data; the only direct human functional readout is the starvation-induced SR Ca²⁺ decrease in patient myoblasts. The precise step from Ca²⁺ dysregulation to myofiber necrosis in human RHABDO1 is inferred, not demonstrated.
  3. Unexplained cardiac sparing. Why humans spare the heart while mice develop cardiomyopathy/arrhythmia is unresolved — likely isoform/redundancy differences, but unproven.
  4. Missense variant interpretation. Most OBSCN missense variants remain VUS; functional assays and segregation data are lacking, and a known cardiomyopathy-"associated" variant (R4344Q) is common in African Americans, cautioning against over-calling pathogenicity.
  5. No disease-specific QoL, prognosis, or therapy data. Management is extrapolated from general rhabdomyolysis care; no clinical trials exist.
  6. No faithful animal model of the human skeletal rhabdomyolysis phenotype exists, hampering therapeutic development.

Proposed Follow-up Experiments / Actions

  1. Establish an international RHABDO1 registry to capture natural history, penetrance, trigger profiles, sex ratio, and outcomes.
  2. Generate a skeletal-muscle-specific, trigger-inducible OBSCN-LOF mouse (or Obscn/Obsl1 conditional) and challenge with exercise/fasting to recapitulate episodic rhabdomyolysis and test why cardiac tissue is spared.
  3. Quantitative SR Ca²⁺ handling assays in patient iPSC-derived myotubes under exercise-/fasting-mimetic stress, measuring SERCA/phospholamban levels and Ca²⁺ transients, to confirm and quantify the human mechanism.
  4. Functional reclassification of OBSCN missense VUS using M-band targeting, titin/myomesin binding, domain stability, and SR Ca²⁺ assays to resolve ACMG classification.
  5. Acylcarnitine/metabolomic profiling of patients to define the metabolic vulnerability (HP:0012071) and its overlap with fatty-acid-oxidation disorders.
  6. Evaluate preventive interventions (structured hydration, graded exercise, nutritional/anti-fasting strategies) in a prospective observational cohort, with CK and episode frequency as endpoints.
  7. Deep phenotyping of heterozygous and homozygous carriers (e.g., the homozygous-carrier mother phenotype) to delineate the expressivity spectrum and dosage sensitivity.

Report compiled from the OBSCN/RHABDO1 primary literature, gnomAD v2.1.1 constraint data, ClinVar (NM_001386125.1), UniProt Q5VST9, and Monarch/HPO disease–phenotype annotations for MONDO:0859371. Evidence types are indicated throughout as human clinical, model organism, in vitro, or computational.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 3
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 32
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 19
Terms named correctly 9
Terms named as a different term 2
Terms whose name is worth a second look 8

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:0859371 (4 mentions) - the report calls it "MONDO"; MONDO calls it rhabdomyolysis, susceptibility to, 1
  • HP:0000083 (3 mentions) - the report calls it "Renal insufficiency", "myoglobinuric AKI"; HP calls it Renal insufficiency

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:

  • HP:0003236 (2 mentions) - the report calls it "Elevated circulating creatine kinase", "markedly elevated serum CK"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated serum CPK" among its other names
  • HP:0010602 (3 mentions) - the report calls it "Type 2 muscle fiber predominance", "type 2 fiber predominance"; HP calls it Type 2 muscle fiber predominance
  • HP:0012071 (4 mentions) - the report calls it "Abnormal circulating fatty acylcarnitine concentration", "abnormal fatty acylcarnitine profile"; HP calls it Abnormal circulating fatty acylcarnitine concentration, and lists "Abnormal fatty acylcarnitine level" among its other names
  • GO:0016529 (2 mentions) - the report calls it "GO cellular component: sarcoplasmic reticulum", "Sarcoplasmic reticulum"; GO calls it sarcoplasmic reticulum**
  • GO:0030018 (2 mentions) - the report calls it "Z-disk"; GO calls it Z disc, and lists "Z disk" among its other names
  • CL:0000188 (2 mentions) - the report calls it "skeletal muscle fibers/myofibers"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
  • UBERON:0002036 (1 mention) - the report calls it "skeletal muscle tissue"; UBERON calls it striated muscle tissue
  • GO:0005739 (1 mention) - the report calls it "mitochondria"; GO calls it mitochondrion, and lists "mitochondria" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0003236 - called "Elevated circulating creatine kinase", "markedly elevated serum CK"
  • HP:0000083 - called "Renal insufficiency", "myoglobinuric AKI"
  • HP:0010602 - called "Type 2 muscle fiber predominance", "type 2 fiber predominance"
  • HP:0002460 - called "Distal muscle weakness", "distal muscle weakness"
  • HP:0012071 - called "Abnormal circulating fatty acylcarnitine concentration", "abnormal fatty acylcarnitine profile"
  • GO:0016529 - called "GO cellular component:** sarcoplasmic reticulum", "Sarcoplasmic reticulum"