Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

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

doi:10.1016/j.ajhg.2023.04.006

Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

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. EstrellaLynn 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	989-997
Number of pages	9
Journal	American journal of human genetics
Volume	110
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2023.04.006
State	Published - Jun 1 2023

Keywords

HMG-CoA reducatase
HMGCR
autoimmune myopathy
limb-girdle like muscular dystrophy
mevalonate pathway
rare genetic disease
statin-induced myopathy

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Morales-Rosado, J. A., Schwab, T. L., Macklin-Mantia, S. K., Foley, A. R., Pinto e Vairo, F., Pehlivan, D., Donkervoort, S., Rosenfeld, J. A., Boyum, G. E., Hu, Y., Cong, A. T. Q., Lotze, T. E., Mohila, C. A., Saade, D., Bharucha-Goebel, D., Chao, K. R., Grunseich, C., Bruels, C. C., Littel, H. R., ... Klee, E. W. (2023). Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy. American journal of human genetics, 110(6), 989-997. https://doi.org/10.1016/j.ajhg.2023.04.006

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 2023, 'Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy', American journal of human genetics, vol. 110, no. 6, pp. 989-997. https://doi.org/10.1016/j.ajhg.2023.04.006

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title = "Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy",

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.",

keywords = "HMG-CoA reducatase, HMGCR, autoimmune myopathy, limb-girdle like muscular dystrophy, mevalonate pathway, rare genetic disease, statin-induced myopathy",

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

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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.

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.

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KW - HMGCR

KW - autoimmune myopathy

KW - limb-girdle like muscular dystrophy

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KW - rare genetic disease

KW - statin-induced myopathy

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Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

Abstract

Keywords

ASJC Scopus subject areas

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