Molecular genetics of mucopolysaccharidosis type I - mutation analysis among the patients of the former Soviet Union

Abstract

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of the lysosomal protein alpha-l-iduronidase (IDUA). Patients present within a broad spectrum of phenotypes from severe (Hurler syndrome) to clinically less severe (Scheie syndrome). Since 1982 a special program for the diagnosis and prevention of lysosomal storage diseases has operated in the former Soviet Union (FSU). We report the genotypes of 25 MPS-I patients with different clinical severities from the FSU. All the patients were screened for two common mutations (W402X and Q70X) and four other mutations (P533R, R89Q, A327P, 474 2a-->g). W402X and Q70X alleles accounted for 4 and 44%, respectively. Using SSCP analysis and subsequent direct sequencing we also detected four novel mutations (P533L, Q63X, Y343X, and A75P) in the IDUA gene, together with two mutations (974ins12bp, 134del12bp) described elsewhere. All were found in the heterozygous form in MPS-I patients with different clinical severities. A total of 32 mutant alleles leading to MPS-I was identified with nine patients fully genotyped. Four patients were homozygous for Q70X while five others were genetic compounds. Besides the eight identified mutations, six known polymorphisms were found. The spectrum of mutant alleles discovered is highly specific and proves the peculiarity of genetic loads in the FSU. Our data suggest a closer relationship between the FSU and Scandinavian populations than with Western and Central European populations.