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Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.
Morales-Rosado, Joel A; Schwab, Tanya L; Macklin-Mantia, Sarah K; Foley, A Reghan; Pinto E Vairo, Filippo; Pehlivan, Davut; Donkervoort, Sandra; Rosenfeld, Jill A; Boyum, Grace E; Hu, Ying; Cong, Anh T Q; Lotze, Timothy E; Mohila, Carrie A; Saade, Dimah; Bharucha-Goebel, Diana; Chao, Katherine R; Grunseich, Christopher; Bruels, Christine C; Littel, Hannah R; Estrella, Elicia A; Pais, Lynn; Kang, Peter B; Zimmermann, Michael T; Lupski, James R; Lee, Brendan; Schellenberg, Matthew J; Clark, Karl J; Wierenga, Klaas J; Bönnemann, Carsten G; Klee, Eric W.
Affiliation
  • Morales-Rosado JA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA.
  • Schwab TL; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
  • Macklin-Mantia SK; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics at Mayo Clinic, Jacksonville, FL, USA.
  • Foley AR; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Pinto E Vairo F; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
  • Pehlivan D; 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.
  • Donkervoort S; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.
  • Boyum GE; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
  • Hu Y; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Cong ATQ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
  • Lotze TE; Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • Mohila CA; Department of Pathology & Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
  • Saade D; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Bharucha-Goebel D; 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.
  • Chao KR; Program in Medical and Population Genetics, Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Grunseich C; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Bruels CC; Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
  • Littel HR; Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
  • Estrella EA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Pais L; 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
  • Kang PB; 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.
  • Zimmermann MT; Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
  • Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
  • Lee B; Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
  • Schellenberg MJ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
  • Clark KJ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MM, USA.
  • Wierenga KJ; Department of Clinical Genomics at Mayo Clinic, Jacksonville, FL, USA.
  • Bönnemann CG; Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Klee EW; 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.
Am J Hum Genet ; 110(6): 989-997, 2023 06 01.
Article in En | MEDLINE | ID: mdl-37167966
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hydroxymethylglutaryl-CoA Reductase Inhibitors / Muscular Dystrophies, Limb-Girdle / Muscular Diseases / Muscular Dystrophies Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: Am J Hum Genet Year: 2023 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Hydroxymethylglutaryl-CoA Reductase Inhibitors / Muscular Dystrophies, Limb-Girdle / Muscular Diseases / Muscular Dystrophies Type of study: Diagnostic_studies / Prognostic_studies Limits: Humans Language: En Journal: Am J Hum Genet Year: 2023 Document type: Article Affiliation country: Estados Unidos