Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.

Détails

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Etat: Serval
Version: de l'auteur
ID Serval
serval:BIB_CC6ABC66BB92
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Evolutionary comparison provides evidence for pathogenicity of RMRP mutations.
Périodique
Plos Genetics
Auteur(s)
Bonafé L., Dermitzakis E.T., Unger S., Greenberg C.R., Campos-Xavier B.A., Zankl A., Ucla C., Antonarakis S.E., Superti-Furga A., Reymond A.
ISSN
1553-7404[electronic]
Statut éditorial
Publié
Date de publication
2005
Peer-reviewed
Oui
Volume
1
Numéro
4
Pages
e47
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation.
Mots-clé
Animals, Base Sequence, Endoribonucleases/genetics, Evolution, Molecular, Family Health, Genome, Genomics, Heterozygote, Homozygote, Humans, Molecular Sequence Data, Mutation, Osteochondrodysplasias/genetics, Polymorphism, Genetic, Promoter Regions, Genetic, RNA/genetics, Sequence Homology, Nucleic Acid
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 16:51
Dernière modification de la notice
09/05/2019 1:20
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