Novel Gene Variants Causing Adult-Onset Mitochondrial Disease and Isolated Complex I Deficiency

Overview

Journal Front Genet

Date 2020 Mar 12

PMID 32158465

Citations 10

Authors

Yi Shiau Ng

Kyle Thompson

Daniela Loher

Sila Hopton

Gavin Falkous

Steven A Hardy

Andrew M Schaefer

Sandip Shaunak

Mark E Roberts

James B Lilleker

Robert W Taylor

Affiliations

Soon will be listed here.

Abstract

Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely frameshift variant in (m.14512_14513del) and a novel maternally-inherited transversion mutation in were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the variant was undetectable while the mutant heteroplasmy level of the variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.

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