The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy

Maria Lucia Valentino, Piero Barboni, Anna Ghelli, Laura Bucchi, Chiara Rengo, Alessandro Achilli, Antonio Torroni, Alessandra Lugaresi, Raffaele Lodi, Bruno Barbiroli, MariaTeresa Dotti, Antonio Federico, Agostino Baruzzi, Valerio Carelli

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)631-641
Number of pages11
JournalAnnals of Neurology
Issue number5
Publication statusPublished - Nov 2004

ASJC Scopus subject areas

  • Neuroscience(all)


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