Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture

BMC Medical Genetics

Research Article

Rachel Straussberg¹  Massimo Buvoli²  Ada Buvoli²  Leslie Anne Leinwand²  Ron Dabby³  Menachem Sadeh³  Ilan Shelef⁴  Miora Feinstein-Linial⁵  Daniel Dayan⁵  Ohad S. Birk⁶ 

[1] Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel;Neurology Institute, Schneider Children’s Medical Center, Petah Tikvah, Israel;Department of Molecular, Cellular and Developmental Biology, University of Colorado, 80309-0347, Boulder, CO, USA;Department of Neurology, Edith Wolfson Medical Center, Holon, Israel;Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel;Diagnostic Imaging Institute, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University, 84101, Beer-Sheva, Israel;The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, 84105, Beer Sheva, Israel;The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, 84105, Beer Sheva, Israel;Genetics Institute, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Beer-Sheva, Israel;

关键词: MYH7;    Laing distal myopathy;    Proline mutations;    Myosin rod;   

DOI  :  10.1186/s12881-016-0315-1

 received in 2016-01-16, accepted in 2016-07-24,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundHuman 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.MethodsClinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging.ResultsUsing 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.ConclusionsThis 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.

【 授权许可】

CC BY   
© The Author(s). 2016