Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum

Am J Hum Genet. 2007 Sep;81(3):519-29. doi: 10.1086/521034. Epub 2007 Aug 6.


Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA-processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell-cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C-->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Bone Diseases, Developmental / diagnosis*
  • Bone Diseases, Developmental / diagnostic imaging
  • Bone Diseases, Developmental / genetics
  • Cartilage / abnormalities
  • Cartilage / diagnostic imaging
  • Cartilage Diseases / diagnostic imaging
  • Cartilage Diseases / genetics
  • Cartilage Diseases / pathology
  • Child
  • Conserved Sequence
  • Dwarfism / diagnosis*
  • Dwarfism / genetics
  • Dwarfism / pathology
  • Endoribonucleases / chemistry
  • Endoribonucleases / genetics*
  • Endoribonucleases / metabolism
  • Female
  • Humans
  • Hypotrichosis / diagnosis*
  • Hypotrichosis / genetics
  • Hypotrichosis / pathology
  • Immunologic Deficiency Syndromes / genetics
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Protein Biosynthesis / genetics
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism
  • RNA, Ribosomal / chemistry
  • RNA, Ribosomal / metabolism
  • Radiography


  • RNA, Messenger
  • RNA, Ribosomal
  • Endoribonucleases
  • mitochondrial RNA-processing endoribonuclease