Novel MT-ND gene variants causing adult-onset mitochondrial disease and isolated complex I deficiency

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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 cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Frontiers in genetics. - 11 (2020) , 24, ISSN: 1664-8021

Keyword: Galerie Lempertz Contempora
Mitochondriale DNS
Muskelkrankheit

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2020

Creator: Ng, Yi Shiau
Thompson, Kyle
Loher, Daniela
Hopton, Sila
Falkous, Gavin
Hardy, Steven A.
Schaefer, Andrew M.
Shaunak, Sandip
Roberts, Mark E.
Lilleker, James B.
Taylor, Robert W.

DOI: 10.3389/fgene.2020.00024

URN: urn:nbn:de:bsz:25-freidok-1586696

Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:52 PM CET

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Ng, Yi Shiau
Thompson, Kyle
Loher, Daniela
Hopton, Sila
Falkous, Gavin
Hardy, Steven A.
Schaefer, Andrew M.
Shaunak, Sandip
Roberts, Mark E.
Lilleker, James B.
Taylor, Robert W.
Universität

Time of origin

2020

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Novel MT-ND gene variants causing adult-onset mitochondrial disease and isolated complex I deficiency

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Other Objects (12)

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