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The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy
Author(s) -
Valentino Maria Lucia,
Barboni Piero,
Ghelli Anna,
Bucchi Laura,
Rengo Chiara,
Achilli Alessandro,
Torroni Antonio,
Lugaresi Alessandra,
Lodi Raffaele,
Barbiroli Bruno,
Dotti MariaTeresa,
Federico Antonio,
Baruzzi Agostino,
Carelli Valerio
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20236
Subject(s) - leber's hereditary optic neuropathy , optic neuropathy , hot spot (computer programming) , medicine , gene , genetics , ophthalmology , biology , optic nerve , computer science , operating system
A novel mitochondrial DNA (mtDNA) transition (3733G→A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G→A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex I to rotenone inhibition. We conclude that the 3733G→A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON. Ann Neurol 2004;56:631–641