Bi-Allelic Loss-Of-Function OBSCN Variants Predispose Individuals to Severe Recurrent Rhabdomyolysis

dc.contributor.authorAydin, Halil Ibrahim
dc.contributor.orcIDhttps://orcid.org/0000-0001-7994-4394en_US
dc.contributor.pubmedID34957489en_US
dc.contributor.researcherIDAHD-1839-2022en_US
dc.date.accessioned2023-09-14T08:51:07Z
dc.date.available2023-09-14T08:51:07Z
dc.date.issued2021
dc.description.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, 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. Cabrera-Serrano et al. show that biallelic loss-of-function variants in the gene encoding obscurin (OBSCN) predispose individuals to recurrent and severe episodes of rhabdomyolysis, typically with onset in the teenage years.en_US
dc.identifier.endpage3998en_US
dc.identifier.issn0006-8950en_US
dc.identifier.issue11en_US
dc.identifier.scopus2-s2.0-85142403734en_US
dc.identifier.startpage3985en_US
dc.identifier.urihttps://watermark.silverchair.com/awab484.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA2swggNnBgkqhkiG9w0BBwagggNYMIIDVAIBADCCA00GCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMVcRj460eWsp9NiaNAgEQgIIDHrnkdL03m9Ib80ttpejCxmKF2Qjy-jQJSJ-lRjqZhSDOc5vTTinWilihz-lDhWJY7Vu9iO_dHuDynZb_J11hCodEuh_rSLgfbnvuFF6WYTWi0mk0soOqKj3fxENAyGJxEzepZW_sPUx0Zz6C339k8jhHmm5WBwaE533aVU-tqG_zxMtEs4AR3w-a50nQP6bOuN1loN0uZxBxkPO2dfK0du_sRVy6G_g1e81Kg_12PPGM6L0zfCcHiBSpUCUZ48uNcRmylb_6W0GX0n5F5WPruFoZmjYSHjbkH26EWSz3hS61eTImqMiCFX_52e4c5FjyL37FNJJEiWJgXmBqy4jNbrNqaq7VOgcnuiUh5P_XKShwcg8j4znXJnvisLAU2LdU64xXcSciLK29irtcP9OS5A4pjN_Z6Uoavs-SB8l5x5hGZaSsTEb0xC7c0f-1miUT3vttRnch3jDMl-HaXY5jYfeXQkR3YBUu5_-gWkiZhK5nW2D9C074zcO1fOM7nnKwyOgzHlXnquZI_6a_s1xmtv08VSVMaAPIsbKMPXQsRsaldUPPsBjMWdvjQFlXaWLWg6uaxJ58MtDEIRccM7VSd8KUKgoyQLoZp5l1rt6QhlVZscUYQbRWJVnMwJ8Mhywe-yUcGxnnuH5qrqSwaBBLV4__Dt3n6dfRGO1dtju_yua96SB8TlLSfQ9O4d4B41QwdwbhXsjjalSiZFq3iVs7l4z-XxTap-H2x9xzeKyRrMEDGcysp5vRbDboSG8uUBn3sAbJ_diEBLwIQKEuwM_0enEZxSUmzd7M4LHjsw1R6p3C1zT14wKAAY-7oMtEuJH2xvPfsM8p0qyNY5_QaVdZfXtqfLVp3M9nSzNAEKxIJBREnceGX21tEcXT-huUPz4VOXu6b_YhxcJgiEBHbuOZUPfj8f36Zzrnh71idiHxaNMLk3XHIsW32kGQ33xq-63oXJurBVnGXaaugFxhQ8jCH3X3ooIAxeTqcDagN8cOeNMaFr0L1Z7gRfcgb5vPYqsR5KWed739tFtzJBVo6HUlm-rEVkzPHgphrmcZerX64Q
dc.identifier.urihttp://hdl.handle.net/11727/10648
dc.identifier.volume145en_US
dc.identifier.wos000839569500001en_US
dc.language.isoengen_US
dc.relation.isversionof10.1093/brain/awab484en_US
dc.relation.journalBRAINen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergien_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectrhabdomyolysisen_US
dc.subjecthyperCKaemiaen_US
dc.subjectmyalgiaen_US
dc.subjectexercise intoleranceen_US
dc.subjectobscurinen_US
dc.titleBi-Allelic Loss-Of-Function OBSCN Variants Predispose Individuals to Severe Recurrent Rhabdomyolysisen_US
dc.typearticleen_US

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