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

Frontiers in Genetics
Yi Shiau NgRobert W Taylor

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 de novo, frameshift variant in MT-ND6 (m.14512_14513del) and a novel maternally-inherited transversion mutation in MT-ND1 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 MT-ND6 variant was undetectable while the mutant heteroplasmy level of the MT-ND1 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 ca...Continue Reading

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Citations

Nov 8, 2020·FEBS Letters·Erika Fernandez-Vizarra, Massimo Zeviani
Jun 20, 2021·Lancet Neurology·Yi Shiau NgDoug M Turnbull

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Methods Mentioned

BETA
urine collection
biopsy
Biopsies
PCR
Electrophoresis

Software Mentioned

Pyromark Q24

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