The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum.

Cartilage-hair hypoplasia and anauxetic dysplasia are two autosomal recessive skeletal dysplasias characterized by different degrees from metaphyseal to spondylo-meta-epiphyseal dysplasia and variable additional features including predisposition to cancer, anemia, immunodeficiency, and gastrointestinal malabsorption and Hirschsprung's disease. Both are caused by mutations in the untranslated RMRP gene, which forms the RNA subunit of the RNase MRP complex. This complex is involved in the ribosome assembly by cleavage of 5.8S rRNA, cell cycle control by Cyclin B2 mRNA cleavage at the end of mitosis, processing the mitochondrial RNA, and forming a complex with hTERT suggesting a possible involvement in expression regulation by siRNA synthesis. The degree of skeletal dysplasia correlates mainly with the rRNA cleavage activity, whereas significantly diminished mRNA cleavage activity is a prerequisite for immunodeficiency. Thus, the clinical phenotype emerges in most cases of the combined effect on the respective effect on RNase MRP function.