Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees.
The mitochondrial DNA (mtDNA) of 87 index cases with Leber hereditary optic neuropathy (LHON) sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, was evaluated in detail. Only seven pairs and three triplets of identical haplotypes were observed, attesting that the large majority of the LHON mutations were due to independent mutational events. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that two specific combinations of amino acid changes in the cytochrome b are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory-chain complexes I and III. The families with identical haplotypes were genealogically reinvestigated, which led to the reconnection into extended pedigrees of three pairs of families, including the Brazilian family with its Italian counterpart. The sequencing of entire mtDNA samples from the reconnected families confirmed the genealogical reconstruction but showed that the Brazilian family was heteroplasmic at two control-region positions. The survey of the two sites in 12 of the Brazilian subjects revealed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination.
Dipartimento di Scienze Neurologiche, Universita di Bologna, Bologna, Italy.
Valerio
V
Carelli
Alessandro
A
Achilli
Maria Lucia
ML
Valentino
Chiara
C
Rengo
Ornella
O
Semino
Maria
M
Pala
Anna
A
Olivieri
Marina
M
Mattiazzi
Francesco
F
Pallotti
Franco
F
Carrara
Massimo
M
Zeviani
Vincenzo
V
Leuzzi
Carla
C
Carducci
Giorgio
G
Valle
Barbara
B
Simionati
Luana
L
Mendieta
Solange
S
Salomao
Rubens
R
Belfort
Alfredo A
AA
Sadun
Antonio
A
Torroni
D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D011995:Recombination, Genetic
D004272:DNA, Mitochondrial