DYSF

Chr 2AR

dysferlin

Also known as: FER1L1, LGMD2B, LGMDR2, MMD1

NCBI Gene: 8291 ENSG00000135636 OMIM: 603009

The encoded protein is a skeletal muscle sarcolemma protein that mediates calcium-dependent membrane fusion events for muscle membrane repair and regeneration, and binds caveolin-3 for caveolae formation. Mutations cause autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular dystrophy, and distal myopathy with anterior tibial onset through a gain-of-function mechanism. These conditions present as progressive muscle weakness affecting different muscle groups depending on the specific phenotype.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.733 OMIM phenotypes

VCEP Guidelines: Limb Girdle Muscular DystrophyReleased

ClinGen Panel

Clinical Summary— DYSF

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Gene-Disease Validity (ClinGen)

autosomal recessive limb-girdle muscular dystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.000

Z-score 4.01

OE 0.60 (0.50–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.04Z-score

OE missense 1.00 (0.95–1.04)

1232 obs / 1235.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.50–0.73)

0≤0.351.4

Missense OE?1.00 (0.95–1.04)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 72 / 119.3Missense obs/exp: 1232 / 1235.8Syn Z: -1.86

This gene — mechanism propensity

0.6647th %ile

GOF

0.72top 25%

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.