Abstract
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.
Highlights
Noonan syndrome (NS) was first described by Noonan and Ehmke [1]
We aimed to address several issues in the present study: (i) to evaluate whether Ras/MAPK pathway syndromes cluster in particular hgs by comparing the data with data available from human populations of the same ancestry, (ii) to identify mutations that could explain the clinical phenotypes of our patients, (iii) to evaluate whether replacement substitutions accumulate to a greater extent in patients with respect to expectations derived from control individuals; (iv) to see whether tRNA mutations are more prevalent in patients than in control individuals, and (v) to examine recurrent, private and heteroplasmic mutations for patterns that could explain the clinical phenotypes
No mutations on the RAF1 gene were identified in negative cases of PTPN11, SOS1, and KRAS
Summary
Noonan syndrome (NS) was first described by Noonan and Ehmke [1] It refers to a pleiomorphic autosomal dominant disorder with short stature, facial dysmorphia, a webbed neck and heart defects, and its prevalence is about one in 1000–2500 live births [2]. 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), 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.
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