title: Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture.
abstract: Human skeletal muscles express three major myosin heavy chain (MyHC) isoforms: MyHCIIx (MYH1) in fast type 2B muscle fibers, MyHCIIa (MYH2) in fast type 2A fibers and MyHCI/β-cardiac MyHC (MYH7) in slow type I skeletal fibers and cardiac ventricles. In line with its expression pattern, MYH7 mutations have been reported in association with hypertrophic or dilated cardiomyopathy, skeletal myopathies or a combination of both. We analyzed the clinical and molecular phenotype of two unrelated families of Jewish Moroccan ancestry that presented with apparently autosomal dominant inheritance of progressive Laing-like distal myopathy with non-specific myopathic changes, but uncommon marked contractures and wasting of the neck extensors.
  
  
  
  Clinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging.
  
  
  
  Using whole exome sequencing we identified in both families two novel heterozygous proline substitutions located in exon 31 of MYH7 within its rod domain: c.4309G>C (p.Ala1437Pro) and c.4301G>C (p.Arg1434Pro). Here we show that the phenotype caused by these mutations includes marked cervical muscle contracture, and report that the severity of the phenotype varies significantly, to the extent of non-penetrance in one of the families. Finally, we provide evidence that both proline substitutions impair myosin self-assembly in non-muscle cells transfected with β-myosin constructs carrying the mutations, but do not prevent incorporation of the mutant molecules into the sarcomere.
  
  
  
  This study expands our clinical and molecular knowledge of MYH7 rod mutations causing skeletal myopathies, and underscores the importance of discussing disease penetrance during genetic counseling.
authors: The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, 84105, Israel.
authors: Miora
authors: M
authors: Feinstein-Linial
authors: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309-0347, USA.
authors: Massimo
authors: M
authors: Buvoli
authors: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309-0347, USA.
authors: Ada
authors: A
authors: Buvoli
authors: Department of Neurology, Edith Wolfson Medical Center, Holon, Israel.|Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors: Menachem
authors: M
authors: Sadeh
authors: Department of Neurology, Edith Wolfson Medical Center, Holon, Israel.|Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
authors: Ron
authors: R
authors: Dabby
authors: Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.|Neurology Institute, Schneider Children's Medical Center, Petah Tikvah, Israel.
authors: Rachel
authors: R
authors: Straussberg
authors: Diagnostic Imaging Institute, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, 84101, Israel.
authors: Ilan
authors: I
authors: Shelef
authors: The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, 84105, Israel.
authors: Daniel
authors: D
authors: Dayan
authors: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309-0347, USA.
authors: Leslie Anne
authors: LA
authors: Leinwand
authors: The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, 84105, Israel. obirk@bgu.ac.il.|Genetics Institute, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84101, Israel. obirk@bgu.ac.il.
authors: Ohad S
authors: OS
authors: Birk
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001415:Back / Q000000981:diagnostic imaging / Q000473:pathology; D019556:COS Cells; D024722:Cardiac Myosins / Q000235:genetics*; D002522:Chlorocebus aethiops; D003286:Contracture / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D009333:Neck / Q000000981:diagnostic imaging / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000235:genetics / Q000378:metabolism*
chemical_list: C501641:MYH7 protein, human; D004247:DNA; D011392:Proline; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: Laing distal myopathy; MYH7; Myosin rod; Proline mutations