RT Journal Article
T1 Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis.
A1 Cabrera-Serrano, Macarena
A1 Caccavelli, Laure
A1 Savarese, Marco
A1 Vihola, Anna
A1 Jokela, Manu
A1 Johari, Mridul
A1 Capiod, Thierry
A1 Madrange, Marine
A1 Bugiardini, Enrico
A1 Brady, Stefen
A1 Quinlivan, Rosaline
A1 Merve, Ashirwad
A1 Scalco, Renata
A1 Hilton-Jones, David
A1 Houlden, Henry
A1 Aydin, Halil Ibrahim
A1 Ceylaner, Serdar
A1 Drewes, Sarah
A1 Vockley, Jerry
A1 Taylor, Rhonda L
A1 Folland, Chiara
A1 Kelly, Aasta
A1 Goullee, Hayley
A1 Ylikallio, Emil
A1 Auranen, Mari
A1 Tyynismaa, Henna
A1 Udd, Bjarne
A1 Forrest, Alistair R R
A1 Davis, Mark R
A1 Bratkovic, Drago
A1 Manton, Nicholas
A1 Robertson, Thomas
A1 O'Gorman, Cullen
A1 McCombe, Pamela
A1 Laing, Nigel G
A1 Phillips, Liza
A1 de Lonlay, Pascale
A1 Ravenscroft, Gianina
K1 exercise intolerance
K1 hyperCKaemia
K1 myalgia
K1 obscurin
K1 rhabdomyolysis
AB 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 10 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 sarcoplasmic reticulum function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic reticulum 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.
YR 2022
FD 2022
LK http://hdl.handle.net/10668/19728
UL http://hdl.handle.net/10668/19728
LA en
DS RISalud
RD Apr 7, 2025