Bi-Allelic Variants in HMGCR Cause an Autosomal-Recessive Progressive Limb-Girdle Muscular Dystrophy

Authors

Joel A Morales-Rosado
Tanya L Schwab
Sarah K Macklin-Mantia
A Reghan Foley
Filippo Pinto E Vairo
Davut Pehlivan
Sandra Donkervoort
Jill A Rosenfeld
Grace E Boyum
Ying Hu
Anh T Q Cong
Timothy E Lotze
Carrie A Mohila
Dimah Saade
Diana Bharucha-Goebel
Katherine R Chao
Christopher Grunseich
Christine C Bruels
Hannah R Littel
Elicia A Estrella
Lynn Pais
Peter B Kang
Michael T Zimmermann
James R Lupski
Brendan Lee
Matthew J Schellenberg
Karl J Clark
Klaas J Wierenga
Carsten G Bönnemann
Eric W Klee

Publication Date

6-1-2023

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2023.04.006

PMID

37167966

PMCID

PMC10257193

PubMedCentral® Posted Date

5-10-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mevalonic Acid, Muscular Dystrophies, Limb-Girdle, Muscular Diseases, Muscular Dystrophies, Oxidoreductases, Hydroxymethylglutaryl CoA Reductases, HMG-CoA reducatase, limb-girdle like muscular dystrophy, rare genetic disease, HMGCR, mevalonate pathway, autoimmune myopathy, statin-induced myopathy

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.