Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy.

Adaptor Proteins, Signal Transducing / genetics Adolescent Adult Asian People / genetics Chromosomes, Human, Pair 19 / genetics DNA Methylation Female Humans Lod Score Male Muscle, Skeletal / diagnostic imaging Muscular Dystrophies / genetics Pedigree RNA-Seq Trinucleotide Repeat Expansion / genetics Tumor Suppressor Protein p53 / metabolism Young Adult

GGC repeat expansions GIPC1 RNA-seq intranuclear inclusions oculopharyngodistal myopathy

Journal

American journal of human genetics

ISSN: 1537-6605

Titre abrégé: Am J Hum Genet

Pays: United States

ID NLM: 0370475

Informations de publication

Date de publication:
04 06 2020

Historique:

received: 21 12 2019

accepted: 15 04 2020

pubmed: 16 5 2020

medline: 9 10 2020

entrez: 16 5 2020

Statut: ppublish

Résumé

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

Identifiants

DOI: 10.1016/j.ajhg.2020.04.011 PMID: 32413282 PMC: PMC7273532

pubmed: 32413282

pii: S0002-9297(20)30120-8

doi: 10.1016/j.ajhg.2020.04.011

pmc: PMC7273532

pii:

doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0

GIPC1 protein, human 0

TP53 protein, human 0

Tumor Suppressor Protein p53 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

793-804

Informations de copyright

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