RT Journal Article
T1 Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes
A1 Gómez Carballa, Alberto
A1 Cerezo Fernández, María
A1 Balboa Beltrán, Emilia
A1 Heredia Ramírez, Claudia Emilia
A1 Castro Feijóo, Lidia
A1 Rica, Itxaso
A1 Barreiro Conde, Jesús
A1 Eirís Puñal, Jesús Manuel
A1 Cabanas Rodríguez, Paloma
A1 Martínez Soto, María Isabel
A1 Fernández Toral, Joaquín
A1 Castro Gago, Manuel
A1 Pombo Arias, Manuel Arturo
A1 Carracedo Álvarez, Ángel
A1 Barros Angueira, Francisco
A1 Salas Ellacuriaga, Antonio
K1 Mitochondrial DNA
K1 Substitution mutation
K1 Phylogenetics
K1 Transfer RNA
K1 Mutation
K1 Mutation detection
K1 Haplogroups
K1 Heredity
AB BackgroundThere are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42).Methods/Principal FindingsThe results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups.Conclusions/SignificanceAs a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.
PB PLOS
YR 2011
FD 2011
LK http://hdl.handle.net/10347/23024
UL http://hdl.handle.net/10347/23024
LA eng
NO Gómez-Carballa A, Cerezo M, Balboa E, Heredia C, Castro-Feijóo L, Rica I, et al. (2011) Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes. PLoS ONE 6(4): e18348. https://doi.org/10.1371/journal.pone.0018348
NO This research received support from two grants from the Fundación de Investigación Médica Mutua Madrileña, and a grant from the Ministerio de Ciencia e Innovación (SAF2008-02971), given to AS
DS Minerva
RD 25 abr 2026