TY - JOUR
T1 - Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy
AU - Morales-Rosado, Joel A.
AU - Schwab, Tanya L.
AU - Macklin-Mantia, Sarah K.
AU - Foley, A. Reghan
AU - Pinto e Vairo, Filippo
AU - Pehlivan, Davut
AU - Donkervoort, Sandra
AU - Rosenfeld, Jill A.
AU - Boyum, Grace E.
AU - Hu, Ying
AU - Cong, Anh T.Q.
AU - Lotze, Timothy E.
AU - Mohila, Carrie A.
AU - Saade, Dimah
AU - Bharucha-Goebel, Diana
AU - Chao, Katherine R.
AU - Grunseich, Christopher
AU - Bruels, Christine C.
AU - Littel, Hannah R.
AU - Estrella, Elicia A.
AU - Pais, Lynn
AU - Kang, Peter B.
AU - Zimmermann, Michael T.
AU - Lupski, James R.
AU - Lee, Brendan
AU - Schellenberg, Matthew J.
AU - Clark, Karl J.
AU - Wierenga, Klaas J.
AU - Bönnemann, Carsten G.
AU - Klee, Eric W.
N1 - Publisher Copyright:
© 2023
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - HMG-CoA reducatase
KW - HMGCR
KW - autoimmune myopathy
KW - limb-girdle like muscular dystrophy
KW - mevalonate pathway
KW - rare genetic disease
KW - statin-induced myopathy
UR - http://www.scopus.com/inward/record.url?scp=85160290739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85160290739&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2023.04.006
DO - 10.1016/j.ajhg.2023.04.006
M3 - Article
C2 - 37167966
AN - SCOPUS:85160290739
SN - 0002-9297
VL - 110
SP - 989
EP - 997
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -
