1. ¹Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
2. ²Division of Medical Genetics, Saitama Children's Medical Center, Iwatsuki, Japan
3. ³Division of Endocrinology and Metabolism, Saitama Children's Medical Center, Iwatsuki, Japan
4. ⁴Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan
5. ⁵Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan
6. ⁶Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan
7. ⁷Department of Pediatrics, Tokyo Metropolitan Hachioji Children's Hospital, Hachioji, Japan
8. ⁸Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Kiyose, Japan

Correspondence: Shiro Ikegawa, Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail: sikegawa@ims.u-tokyo.ac.jp

^*Yuichiro Hirose and Eiji Nakashima contributed equally to this work.

Received 18 April 2006; Accepted 10 May 2006; Published online 11 July 2006.

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.