Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X [fra(X)] mental retardation syndrome is the most frequent familial cause of mental handicap. The clinical phenotype is associated with a rare fragile site at Xq27.3. The mutation underlying the disorder, an insertion into the FMR-1 gene, has been characterized, but the pathogenesis of the condition is obscure and the pattern of inheritance is still not fully understood. One model of fra(X) pathogenesis was proposed by Laird in 1987, suggesting that the fra(X) mutation acts as a cis-acting, local block to the pre-oogenesis reactivation of the inactivated X chromosome. To test this model, we examined the activity of the F8, F9 and iduronate sulphatase (IDS) loci. The level of IDS in the serum of fra(X) males was found to be very significantly reduced in the fra(X) group when compared to that of control males: this lends support to Laird's model of fra(X) pathogenesis. However, we detected no methylation differences between fra(X) and control samples at the IDS locus, although such changes are known in fra(X) males at sites closer to the fragile site. Thus the mechanism of the reduction in IDS activity has not been identified.
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PMID:Fragile X mental retardation and the iduronate sulphatase locus: testing Laird's model of fra(X) inheritance. 160 4

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.
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PMID:Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency. 855 71