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Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy. Am J Hum Genet 2023 Jun 01;110(6):989-997

Date

05/12/2023

Pubmed ID

37167966

Pubmed Central ID

PMC10257193

DOI

10.1016/j.ajhg.2023.04.006

Scopus ID

2-s2.0-85160290739 (requires institutional sign-in at Scopus site)   2 Citations

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.

Author List

Morales-Rosado JA, Schwab TL, Macklin-Mantia SK, Foley AR, Pinto E Vairo F, Pehlivan D, Donkervoort S, Rosenfeld JA, Boyum GE, Hu Y, Cong ATQ, Lotze TE, Mohila CA, Saade D, Bharucha-Goebel D, Chao KR, Grunseich C, Bruels CC, Littel HR, Estrella EA, Pais L, Kang PB, Zimmermann MT, Lupski JR, Lee B, Schellenberg MJ, Clark KJ, Wierenga KJ, Bönnemann CG, Klee EW

Author

Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Humans
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mevalonic Acid
Muscular Diseases
Muscular Dystrophies
Muscular Dystrophies, Limb-Girdle
Oxidoreductases