Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
Am J Hum Genet
; 110(6): 989-997, 2023 06 01.
Article
in En
| MEDLINE
| ID: mdl-37167966
ABSTRACT
Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/
Muscular Dystrophies, Limb-Girdle
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Muscular Diseases
/
Muscular Dystrophies
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Am J Hum Genet
Year:
2023
Type:
Article
Affiliation country:
United States