2. Academic Validation
  3. Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis

Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis

  • Am J Hum Genet. 2020 Aug 6;107(2):293-310. doi: 10.1016/j.ajhg.2020.06.014.
Jessica X Chong 1,  Jared C Talbot 2,  Emily M Teets 3,  Samantha Previs 4,  Brit L Martin 5,  Kathryn M Shively 6,  Colby T Marvin 6,  Arthur S Aylsworth 7,  Reem Saadeh-Haddad 8,  Ulrich A Schatz 9,  Francesca Inzana 10,  Tawfeg Ben-Omran 11,  Fatima Almusafri 11,  Mariam Al-Mulla 11,  Kati J Buckingham 6,  Tamar Harel 12,  Hagar Mor-Shaked 12,  Periyasamy Radhakrishnan 13,  Katta M Girisha 13,  Shalini S Nayak 13,  Anju Shukla 13,  Klaus Dieterich 14,  Julien Faure 15,  John Rendu 15,  Yline Capri 16,  Xenia Latypova 15,  Deborah A Nickerson 17,  David M Warshaw 4,  Paul M L Janssen 5,  University of Washington Center for Mendelian Genomics,  Sharon L Amacher 18,  Michael J Bamshad 19
Affiliations

Affiliations

  • 1 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA.
  • 2 Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus OH 43210, USA. Electronic address: [email protected].
  • 3 Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA.
  • 4 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, USA.
  • 5 Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA.
  • 6 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 7 Departments of Pediatrics and Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 8 Division of Genetics, Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC 20007, USA.
  • 9 Human Genetics, Medical University, Innsbruck 6020, Austria.
  • 10 Genetic Counseling Service, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano 39100, Italy.
  • 11 Division of Genetic and Genomic Medicine, Sidra Medicine and Hamad Medical Corporation, PO Box 3050, Doha, Qatar.
  • 12 Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
  • 13 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
  • 14 Department of Medical Genetics, CHU Grenoble Alpes, Génétique Médicale, Grenoble 38700, France; Université Grenoble Alpes, Inserm, U1216, Grenoble Institut des Neurosciences, Grenoble 38706, France.
  • 15 Université Grenoble Alpes, Inserm, U1216, Grenoble Institut des Neurosciences, Grenoble 38706, France; Biochimie Génétique et Moléculaire, CHU Grenoble Alpes, Grenoble 38700, France.
  • 16 Department of Genetics, APHP-Robert DEBRE University Hospital, UF Génétique clinique, Paris 75019, France.
  • 17 Brotman-Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 18 Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA; Center for Muscle Health and Neuromuscular Disorders, Columbus OH 43210, USA; Dept of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA; Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA.
  • 19 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Brotman-Baty Institute, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: [email protected].
PMID: 32707087 DOI: 10.1016/j.ajhg.2020.06.014
Abstract

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of Myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with Myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced Myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

Keywords

Mendelian disease; amyoplasia; congenital contractures; development; distal arthrogryposis; exome sequencing; myosin; skeletal muscle; zebrafish.

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