title: Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes.
abstract: BACKGROUND
  There 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).
  
  
  RESULTS
  The 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
  As 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.
authors.affiliation: Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, and Instituto de Medicina Legal, Facultade de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, Galicia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gómez-Carballa
authors.forename: María
authors.initials: M
authors.lastname: Cerezo
authors.forename: Emilia
authors.initials: E
authors.lastname: Balboa
authors.forename: Claudia
authors.initials: C
authors.lastname: Heredia
authors.forename: Lidia
authors.initials: L
authors.lastname: Castro-Feijóo
authors.forename: Itxaso
authors.initials: I
authors.lastname: Rica
authors.forename: Jesús
authors.initials: J
authors.lastname: Barreiro
authors.forename: Jesús
authors.initials: J
authors.lastname: Eirís
authors.forename: Paloma
authors.initials: P
authors.lastname: Cabanas
authors.forename: Isabel
authors.initials: I
authors.lastname: Martínez-Soto
authors.forename: Joaquín
authors.initials: J
authors.lastname: Fernández-Toral
authors.forename: Manuel
authors.initials: M
authors.lastname: Castro-Gago
authors.forename: Manuel
authors.initials: M
authors.lastname: Pombo
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
mesh_terms: D002467:Cell Nucleus / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D010802:Phylogeny; D058974:Phylogeography; D012343:RNA, Transfer / Q000235:genetics; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012343:RNA, Transfer; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins