TY - JOUR
T1 - Haplogroup effects and recombination of mitochondrial DNA
T2 - Novel clues from the analysis of leber hereditary optic neuropathy pedigrees
AU - Carelli, Valerio
AU - Achilli, Alessandro
AU - Valentino, Maria Lucia
AU - Rengo, Chiara
AU - Semino, Ornella
AU - Pala, Maria
AU - Olivieri, Anna
AU - Mattiazzi, Marina
AU - Pallotti, Francesco
AU - Carrara, Franco
AU - Zeviani, Massimo
AU - Leuzzi, Vincenzo
AU - Carducci, Carla
AU - Valle, Giorgio
AU - Simionati, Barbara
AU - Mendieta, Luana
AU - Salomao, Solange
AU - Belfort, Rubens
AU - Sadun, Alfredo A.
AU - Torroni, Antonio
PY - 2006/4/1
Y1 - 2006/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33645344999&partnerID=8YFLogxK
U2 - 10.1086/501236
DO - 10.1086/501236
M3 - Article
C2 - 16532388
AN - SCOPUS:33645344999
VL - 78
SP - 564
EP - 574
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -