Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation

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 anchori...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2017-02, Vol.25 (2), p.262-266
Main Authors: Baumann, Matthias, Steichen-Gersdorf, Elisabeth, Krabichler, Birgit, Petersen, Britt-Sabina, Weber, Ulrike, Schmidt, Wolfgang M, Zschocke, Johannes, Müller, Thomas, Bittner, Reginald E, Janecke, Andreas R
Format: Article
Language:English
Subjects:
Age
Arthrogryposis
Arthrogryposis - diagnosis
Arthrogryposis - genetics
Ataxia
Cardiomyopathy
Cerebellar ataxia
Cerebellum
Child
Codon, Nonsense
Congenital diseases
Cytoskeleton
Envelope protein
Genetics
Genotype
Genotypes
Homology
Homozygote
Humans
Isoforms
Kinases
Male
Muscle Weakness - diagnosis
Muscle Weakness - genetics
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscular dystrophy
Mutation
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neuromuscular diseases
Nonsense mutation
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Pediatrics
Pedigree
Phenotype
Phenotypes
Proteins
Short Report
Skeletal muscle
Spectrin
Syndrome
Transcription
Ultrasonic imaging
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Summary: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).
ISSN:1018-4813
1476-5438
DOI:10.1038/ejhg.2016.144