Evolutionary comparison provides evidence for pathogenicity of RMRP mutations

Bonafe, Luisa, Dermitzakis, Emmanouil T., Unger, Sheila, Greenberg, Cheryl R., Campos-Xavier, Belinda A., Zankl, Andreas, Ucla, Catherine, Antonarakis, Stylianos E., Superti-Furga, Andrea and Reymond, Alexandre (2005) Evolutionary comparison provides evidence for pathogenicity of RMRP mutations. PLoS Genetics, 1 4: e47-1-e47-11. doi:10.1371/journal.pgen.0010047

Author Bonafe, Luisa
Dermitzakis, Emmanouil T.
Unger, Sheila
Greenberg, Cheryl R.
Campos-Xavier, Belinda A.
Zankl, Andreas
Ucla, Catherine
Antonarakis, Stylianos E.
Superti-Furga, Andrea
Reymond, Alexandre
Title Evolutionary comparison provides evidence for pathogenicity of RMRP mutations
Formatted title
Evolutionary comparison provides evidence for pathogenicity of RMRP mutations
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2005-10-01
Sub-type Article (original research)
DOI 10.1371/journal.pgen.0010047
Open Access Status DOI
Volume 1
Issue 4
Start page e47-1
End page e47-11
Total pages 11
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Subject 110311 Medical Genetics (excl. Cancer Genetics)
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
Abstract 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.
Keyword Cartilage-hair hypoplasia
recessive mutations
RMRP gene
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
UQ Centre for Clinical Research Publications
ERA 2012 Admin Only
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Citation counts: TR Web of Science Citation Count  Cited 36 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 14 Jan 2010, 01:17:47 EST by Maria Campbell on behalf of Faculty Of Health Sciences