Identification of novel RMRP mutations and specific founder haplotypes in Japanese patients with cartilage-hair hypoplasia

Abstract

Cartilage-hair hypoplasia (CHH), or metaphyseal dysplasia, McKusick type, is an autosomal recessive disease with diverse clinical manifestations.CHH is caused by mutations in RMRP (ribonuclease mitochondrial RNA processing), the gene encoding the RNA component of the ribonucleoprotein complex RNase MRP. A common founder mutation, 70A>G has been reported in the Finnish and Amish populations. We screened 11 Japanese patients with CHH for RMRP mutations and identified mutations in five probands, including three novel mutations (16-bp dup at +1, 168G>A, and 217C>T). All patients were compound heterozygotes for an insertion or duplication in the promoter or 5¢-transcribed regions and a point mutation in the transcribed region. Two recurrent mutations were unique to the Japanese population: a 17-bp duplication at +3 and 218A>G. Haplotype analysis revealed that the two mutations common in Japanese individuals were contained within distinct haplotypes. Through this analysis, we have identified a unique mutation spectrum and founder mutations in the Japanese population.

Of proteins and RNA: The RNase P/MRP family

“…Incapacitating mutations within the RNA component of RNase MRP are found in a wide range of positions and may include various substitutions, duplications, insertions, and deletions, typically in phylogenetically conserved regions of RNA (Bonafé et al 2005;Hermanns et al 2006;Hirose et al 2006;Martin and Li 2007, and references therein). The type and severity of clinical manifestations are apparently defined by the type/localization of the mutations in the two affected alleles.…”

RNase MRP RNA and human genetic diseases

“…The most frequently found mutation is the 70A→G point mutation [11][12][13][14][15][16][17]. Other mutations that have been recorded in patients with CHH are summarized in Table 1.…”

Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations

“…6 A common 70A>G mutation has been identified in 92% of Finnish and 48% of non-Finnish CHH patients 7 ; however, more than 70 different mutations have been identified worlwide. [6][7][8][9][10][11][12][13][14][15] Disease-causing mutations in the RMRP gene result in disruption of ribosomal processing and cell cycle progression in rapidly dividing cells such as lymphocytes and chondrocytes, thus explaining the pleiotropy of clinical manifestations. 6,13,14,16,17 A variable degree of immunodeficiency has been reported in CHH that predominantly affects cell-mediated immunity.…”

“…[6][7][8][9][10][11][12][13][14][15] Disease-causing mutations in the RMRP gene result in disruption of ribosomal processing and cell cycle progression in rapidly dividing cells such as lymphocytes and chondrocytes, thus explaining the pleiotropy of clinical manifestations. 6,13,14,16,17 A variable degree of immunodeficiency has been reported in CHH that predominantly affects cell-mediated immunity. 2,18,19 Some affected individuals have been shown to present with severe combined immunodeficiency (SCID), prompting the need for hematopoietic cell transplantation (HCT).…”