PhenoModifier-Variant Detail

Variant "ACTN3:c.1729C>T(p.Arg577*)"

Search result: 1 record

Variant information

Gene:

ACTN3

Variant:

ACTN3:c.1729C>T(p.Arg577*)

dbSNP ID:

rs1815739

GWAS trait:

blood protein measurement

Modifier statisitcs

Record:

1

Disorder:

1

Reference:

1

Effect type:

Penetrance(1)

Modifier effect:

Altered incidence(1)

Detail：

Target disease:

Duchenne Muscular Dystrophy (DOID_11723)

Effect type:

Penetrance

Modifier effect:

Altered incidence

Evidence:

Study on animal models

Effect:

The α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.

Reference:

PMID28139640

Title:

Evidence for ACTN3 as a genetic modifier of Duchenne muscular dystrophy.

Species studied:

Human

Abstract:

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.