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.
Cartilage-hair hypoplasia is a genetic condition named after two of its most conspicuous features, short bones and sparse hair, but it affects blood-forming tissues, immune system, and intestine. It is caused by sequence mutations in RMRP, a small gene that codes for a structural RNA component of an RNAse complex whose biological functions have been elusive so far. The small RMRP gene carries a surprisingly high number of sequence variations, and because its transcript is not translated into protein and its function in the cell is still unclear, distinction between harmless variants and disease-causing mutations (more than 60 have been found so far by the authors and others) is difficult. The authors have sequenced the RMRP gene in several species covering the whole class of mammals and found that the gene is remarkably conserved between species. Interestingly, mutations occurring in conserved (probably functionally important) regions of the gene appear to be disease-producing, whereas those occurring in regions where evolution is more relaxed seem to be harmless variants. These results will help in counseling affected individuals and their families, and may lead to the discovery of the real function of this mysterious gene.