Biallelic loss-of-function OBSCN variants predispose individuals to severe, recurrent rhabdomyolysis
Author:
Cabrera-Serrano Macarena, Caccavelli Laure, Savarese Marco, Vihola Anna, Jokela Manu, Johari Mridul, Capiod Thierry, Madrange Marine, Bugiardini EnricoORCID, Brady Stefen, Quinlivan Rosaline, Merve Ashirwad, Scalco Renata, Hilton-Jones David, Houlden Henry, Aydin Halil, Ceylaner Serdar, Vockley Jerry, Taylor Rhonda L, Goullee Hayley, Ylikallio Emil, Auranen Mari, Tyynismaa Henna, Udd Bjarne, Forrest Alistair RR, Davis Mark R, Bratkovic Drago, Manton Nicholas, Robertson Thomas, McCombe Pamela, Laing Nigel G, Phillips Liza, de Lonlay Pascale, Ravenscroft GianinaORCID
Abstract
ABSTRACTRhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, the majority of cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) co-segregating with disease. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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