Novel MT-ND gene variants causing adult-onset mitochondrial disease and isolated complex I deficiency
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
- Standort
-
Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
-
Online-Ressource
- Sprache
-
Englisch
- Anmerkungen
-
Frontiers in genetics. - 11 (2020) , 24, ISSN: 1664-8021
- Schlagwort
- Ereignis
-
Veröffentlichung
- (wo)
-
Freiburg
- (wer)
-
Universität
- (wann)
-
2020
- Urheber
-
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
- Rechteinformation
-
Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
-
25.03.2025, 13:52 MEZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- 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
Entstanden
- 2020
Ähnliche Objekte (12)
Bi-allelic mutations in NDUFA6 establish its role in early-onset isolated mitochondrial complex I deficiency
Deleterious variants in WNT10A, EDAR, and EDA causing isolated and syndromic tooth agenesis: a structural perspective from molecular dynamics simulations
Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome
Diagnosis and characterization of leptin mutations causing severe early-onset obesity
Inactivation of thermo-resistant bacteriophages causing fermentation failure and flavor deficiency
Dominant VPS16 pathogenic variants: not only isolated dystonia
Categorization and classification of different ABCA3 variants causing interstitial lung disease
Cerebellar and Midbrain Lysosomal Enzyme Deficiency in Isolated Dystonia
Characterization of novel TOR1A variants causing extreme phenotypes of arthrogryposis multiplex congenita
Computational interpretation of disease-causing, structural, and non-coding human genetic variants
Late-onset antibody deficiency due to monoallelic alterations in NFKB1
Variants of early-onset restrictive eating disturbances in middle childhood
Bi-allelic mutations in NDUFA6 establish its role in early-onset isolated mitochondrial complex I deficiency
Deleterious variants in WNT10A, EDAR, and EDA causing isolated and syndromic tooth agenesis: a structural perspective from molecular dynamics simulations
Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome
Diagnosis and characterization of leptin mutations causing severe early-onset obesity
Inactivation of thermo-resistant bacteriophages causing fermentation failure and flavor deficiency
Dominant VPS16 pathogenic variants: not only isolated dystonia
Categorization and classification of different ABCA3 variants causing interstitial lung disease
Cerebellar and Midbrain Lysosomal Enzyme Deficiency in Isolated Dystonia
Characterization of novel TOR1A variants causing extreme phenotypes of arthrogryposis multiplex congenita
Computational interpretation of disease-causing, structural, and non-coding human genetic variants
Late-onset antibody deficiency due to monoallelic alterations in NFKB1
Variants of early-onset restrictive eating disturbances in middle childhood
Bi-allelic mutations in NDUFA6 establish its role in early-onset isolated mitochondrial complex I deficiency
Deleterious variants in WNT10A, EDAR, and EDA causing isolated and syndromic tooth agenesis: a structural perspective from molecular dynamics simulations
Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome
Diagnosis and characterization of leptin mutations causing severe early-onset obesity
Inactivation of thermo-resistant bacteriophages causing fermentation failure and flavor deficiency
Dominant VPS16 pathogenic variants: not only isolated dystonia
Categorization and classification of different ABCA3 variants causing interstitial lung disease
Cerebellar and Midbrain Lysosomal Enzyme Deficiency in Isolated Dystonia
Characterization of novel TOR1A variants causing extreme phenotypes of arthrogryposis multiplex congenita
Computational interpretation of disease-causing, structural, and non-coding human genetic variants
Late-onset antibody deficiency due to monoallelic alterations in NFKB1