RGD Reference Report - Leber's hereditary optic neuropathy is associated with the T3866C mutation in mitochondrial ND1 gene in three Han Chinese Families. - Rat Genome Database

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Leber's hereditary optic neuropathy is associated with the T3866C mutation in mitochondrial ND1 gene in three Han Chinese Families.

Authors: Zhou, X  Qian, Y  Zhang, J  Tong, Y  Jiang, P  Liang, M  Dai, X  Zhou, H  Zhao, F  Ji, Y  Mo, JQ  Qu, J  Guan, MX 
Citation: Zhou X, etal., Invest Ophthalmol Vis Sci. 2012 Jul 9;53(8):4586-94. doi: 10.1167/iovs.11-9109.
RGD ID: 8657116
Pubmed: PMID:22577081   (View Abstract at PubMed)
PMCID: PMC3394694   (View Article at PubMed Central)
DOI: DOI:10.1167/iovs.11-9109   (Journal Full-text)

PURPOSE: To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON). METHODS: Seventy-one subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of the rates of endogenous, substrate-dependent respirations, the adenosine triphosphate (ATP) production and generation of reactive oxygen species using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects. RESULTS: Ten of 41 matrilineal relatives exhibited variable severity and age at onset of optic neuropathy. The average age at onset of optic neuropathy in matrilineal relatives of the three families was 5, 11, and 24 years, respectively. Molecular analysis identified the ND1 T3866C (I187T) mutation and distinct sets of polymorphisms belonging to the Eastern Asian haplogroups D4a, M10a, and R, respectively. The I187T mutation is localized at the highly conserved isoleucine at a transmembrane domain of the ND1 polypeptide. The marked reductions in the rate of endogenous, malate/glutamate-promoted and succinate/glycerol-3-phosphate-promoted respiration were observed in mutant cell lines carrying the T3866C mutation. The deficient respiration is responsible for the reduced ATP synthesis and increased generation of reactive oxygen species. CONCLUSIONS: Our data convincingly show that the ND1 T3866C mutation leads to LHON. This mutation may be insufficient to produce a clinical phenotype. Other modifier factors may contribute to the phenotypic manifestation of the T3866C mutation. The T3866C mutation should be added to the list of inherited factors for molecular diagnosis of LHON. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Leber hereditary optic neuropathy  IAGP 8657116DNA:missense mutation:cds:m.3866T>C (p.I187T) (human)RGD 
Leber hereditary optic neuropathy  ISOMT-ND1 (Homo sapiens)8657116; 8657116DNA:missense mutation:cds:m.3866T>C (p.I187T) (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Leber optic atrophy  IAGP 8657116DNA:missense mutation:cds:m.3866T>C (p.I187T)RGD 
Reduced visual acuity  IAGP 8657116DNA:missense mutation:cds:m.3866T>C (p.I187T)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Mt-nd1  (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1)

Genes (Mus musculus)
mt-Nd1  (NADH dehydrogenase 1, mitochondrial)

Genes (Homo sapiens)
MT-ND1  (mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1)


Additional Information