Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency.

Mucopolysaccharidosis type I (i.e., Hurler, Hurler-Scheie, and Scheie syndromes) and type II (i.e., Hunter syndrome) are lysosomal storage disorders resulting from alpha-L-iduronidase (IDUA) deficiency and iduronate-2-sulfatase (IDS) deficiency, respectively. The a priori probability that both disorders would occur in a single individual is approximately 1 in 5 billion. Nevertheless, such a proband was referred for whom clinical findings (i.e., a male with characteristic facies, dysostosis multiplex, and mental retardation) and biochemical tests indicated these concomitant diagnoses. In repeated studies, leukocyte 4 methylumbelliferyl-alpha-L-iduronidase activities in this kindred were as follows: <1.0 nmol/mg protein/h in the proband and proband's clinically normal sister; 45.3 in mother; and 45.7 in father (normal range 65.0-140). Leukocyte L-O-(alpha-iduronate-2-sulfate)-(1->4)-D-O-2,5-anhydro[1-3H]mannitol-6- sulfate activities were as follows: 0.0 U/mg protein/h in the proband; 5.7 in his sister; 4.9 in mother; and 15.0 in father (normal range 11.0-18.4). Multiple techniques, including automated sequencing of the entire IDS and IDUA coding regions, were employed to unravel the molecular genetic basis of these intriguing observations. The common IDS mutation R468W was identified in the proband, his mother, and his sister, thus explaining their biochemical phenotypes. Additionally, the proband, his sister, and his father were found to be heterozygous for a common IDUA mutation, W402X. Notably, a new IDUA mutation A300T was also identified in the proband, his sister, and his mother, accounting for reduced IDUA activity in these individuals; the asymptomatic sister, whose cells demonstrated normal glycosaminoglycan metabolism, is thus a compound heterozygote for W402X and the new allele. This A300T mutation is the first IDUA pseudodeficiency gene to be elucidated at the molecular level.