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Lookup NU author(s): Dr Ana Topf,
Professor Volker Straub
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2019 American Academy of Neurology. Objective: To study the genetic and phenotypic spectrum of patients harboring recessive mutations in BVES. Methods: We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in BVES. Results: We identified 4 individuals from 3 families harboring homozygous LOF variants in BVES, the gene that encodes for Popeye domain containing protein 1 (POPDC1). Patients showed skeletal muscle involvement and cardiac conduction abnormalities of varying nature and severity, but all exhibited at least subclinical signs of both skeletal muscle and cardiac disease. All identified mutations lead to a partial or complete loss of function of BVES through nonsense-mediated decay or through functional changes to the POPDC1 protein. Conclusions: We report the identification of homozygous LOF mutations in BVES, causal in a young adult-onset myopathy with concomitant cardiac conduction disorders in the absence of structural heart disease. These findings underline the role of POPDC1, and by extension, other members of this protein family, in striated muscle physiology and disease. This disorder appears to have a low prevalence, although it is probably underdiagnosed because of its striking phenotypic variability and often subtle yet clinically relevant manifestations, particularly concerning the cardiac conduction abnormalities.
Author(s): De Ridder W, Nelson I, Asselbergh B, De Paepe B, Beuvin M, Ben Yaou R, Masson C, Boland A, Deleuze J-F, Maisonobe T, Eymard B, Symoens S, Schindler R, Brand T, Johnson K, Topf A, Straub V, De Jonghe P, De Bleecker JL, Bonne G, Baets J
Publication type: Article
Publication status: Published
Journal: Neurology: Genetics
Online publication date: 01/04/2019
Acceptance date: 12/02/2019
Date deposited: 14/05/2019
ISSN (electronic): 2376-7839
Publisher: Lippincott Williams and Wilkins
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