title: Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation.
abstract: The exceptionally large SYNE1 (spectrin repeat-containing nuclear envelope protein 1) gene encodes different nesprin-1 isoforms, which are differentially expressed in striated muscle and in cerebellar and cerebral neurons. Nesprin-1 isoforms can function in cytoskeletal, nuclear, and vesicle anchoring. SYNE1 variants have been associated with a spectrum of neurological and neuromuscular disease. Homozygosity mapping combined with exome sequencing identified a disease-causing nonsense mutation in the ultimate exon of full-length SYNE1 transcript in an 8-year-old boy with distal arthrogryposis and muscular hypotonia. mRNA analysis showed that the mutant transcript is expressed at wild-type levels. The variant truncates nesprin-1 isoforms for the C-terminal KASH (Klarsicht-ANC-Syne homology) domain. This is the third family with recessive arthrogryposis caused by homozygous distal-truncating SYNE1 variants. There is a SYNE1 genotype-phenotype correlation emerging, with more proximal homozygous SYNE1 variants causing recessive cerebellar ataxia of variable onset (SCAR8; ARCA-1).
authors: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors: Matthias
authors: M
authors: Baumann
authors: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors: Elisabeth
authors: E
authors: Steichen-Gersdorf
authors: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Birgit
authors: B
authors: Krabichler
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors: Britt-Sabina
authors: 0000-0001-9022-9017
authors: BS
authors: Petersen
authors: Department of Pediatrics, Krankenhaus Dornbirn, Dornbirn, Austria.
authors: Ulrike
authors: U
authors: Weber
authors: Neuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors: Wolfgang M
authors: WM
authors: Schmidt
authors: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Johannes
authors: J
authors: Zschocke
authors: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors: Thomas
authors: T
authors: Müller
authors: Neuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors: Reginald E
authors: RE
authors: Bittner
authors: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.|Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Andreas R
authors: 0000-0001-7155-0315
authors: AR
authors: Janecke
mesh_terms: D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
chemical_list: D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C415465:SYNE1 protein, human