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

Am J Hum Genet. 2023 Jun 1;110(6):989-997. doi: 10.1016/j.ajhg.2023.04.006. Epub 2023 May 10.

Authors

Joel A Morales-Rosado¹, Tanya L Schwab², Sarah K Macklin-Mantia³, A Reghan Foley⁴, Filippo Pinto E Vairo⁵, Davut Pehlivan⁶, Sandra Donkervoort⁴, Jill A Rosenfeld⁷, Grace E Boyum⁸, Ying Hu⁴, Anh T Q Cong⁸, Timothy E Lotze⁹, Carrie A Mohila¹⁰, Dimah Saade⁴, Diana Bharucha-Goebel¹¹, Katherine R Chao¹², Christopher Grunseich⁴, Christine C Bruels¹³, Hannah R Littel¹³, Elicia A Estrella¹⁴, Lynn Pais¹⁵, Peter B Kang¹⁶, Michael T Zimmermann¹⁷, James R Lupski¹⁸, Brendan Lee¹⁸, Matthew J Schellenberg⁸, Karl J Clark⁸, Klaas J Wierenga¹⁹, Carsten G Bönnemann⁴, Eric W Klee²⁰

Affiliations

¹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
² Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
³ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics at Mayo Clinic, Jacksonville, FL, USA.
⁴ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
⁵ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.
⁸ Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
⁹ Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁰ Department of Pathology & Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
¹¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Division of Neurology, Children's National Hospital, Washington, DC, USA.
¹² Program in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
¹⁴ Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ Program in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA; Analytic and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA.
¹⁷ Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
¹⁹ Department of Clinical Genomics at Mayo Clinic, Jacksonville, FL, USA.
²⁰ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. Electronic address: klee.eric@mayo.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Humans
Hydroxymethylglutaryl CoA Reductases / adverse effects
Hydroxymethylglutaryl CoA Reductases / genetics
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
Mevalonic Acid
Muscular Diseases* / genetics
Muscular Dystrophies*
Muscular Dystrophies, Limb-Girdle* / diagnosis
Muscular Dystrophies, Limb-Girdle* / genetics
Oxidoreductases

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mevalonic Acid
Oxidoreductases
HMGCR protein, human
Hydroxymethylglutaryl CoA Reductases

Abstract

Publication types

MeSH terms

Substances

Grants and funding