Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis

Abstract

Rhabdomyolysis 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, most 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) predisposing individuals to recurrent rhabdomyolysis. 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.

Combined loss of obscurin and obscurin-like 1 in murine hearts results in diastolic dysfunction, altered metabolism and deregulated mitophagy

“…However, unchanged E/A ratios even in older animals suggest no diastolic dysfunction in R4344Q mice. Intriguingly, there are reports of patients with a bi-allelic loss of obscurin that predispose these individuals to recurrent rhabdomyolysis 35 . Data from our obscurin knockout mice support the finding for the benign cardiac phenotype in affected patients.…”

“…Deletion of obscurin Ig58-59 resulted in an arrhythmogenic cardiomyopathy in aged mice 33 . Patients with bi-allelic loss of obscurin were recently shown to predispose affected individuals to severe recurrent rhabdomyolysis 35 . Consequently, these patients are exercise intolerant.…”

Recent advances in our understanding of genetic rhabdomyolysis

“…cDNA studies, RNA-seq and western blotting showed substantial reduction in OBSCN expression and protein abundance in patient muscle, confirming that the likely pathomechanism was loss of obscurin function. Preliminary studies in patient myoblasts showed impaired SR refilling under stress conditions [30 ▪▪ ]. In further evidence that obscurin plays a role in Ca 2+ handling, Pierantozzi et al [31] showed slower sarcoplasmic reticulum Ca 2+ release and SERCA reuptake rates in Obscn null mouse myofibres.…”

“…Triggers in some cases included exercise (even mild exercise) and/or heat; in two cases, the episodes appeared to occur spontaneously. Between episodes, serum CK levels were mildly elevated or within normal limits [30 ▪▪ ]. Three cases were elite level athletes in their youth, representing their sport at the national or international level.…”

“…In six unrelated probands with severe and recurrent episodes of rhabdomyolysis typically starting in adolescence, Cabrera-Serrano et al [30 ▪▪ ] identified bi-allelic loss-of-function variants in the gene ( OBSCN ) encoding the giant and enigmatic skeletal muscle protein, obscurin [29,30 ▪▪ ]. Triggers in some cases included exercise (even mild exercise) and/or heat; in two cases, the episodes appeared to occur spontaneously.…”