Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: Multiple allelic mutations of the IDUA gene in a small geographic area
- Hadassah Medical Center, Jerusalem (Israel)
- Univ. of California School of Medicine, Los Angeles (United States)
The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly[sub 409][yields]Arg in exon 9 and Ter[yields]Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr[sub 64][yields]Ter), exon 7 (Gln[sub 310][yields]Ter), or exon 8 (Thr[sub 366][yields]Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr[sub 366][yields]Pro and Ter[yields]Cys, permitted the expression of only trace amounts of [alpha]-L-iduronidase activity, whereas Gly[sub 409][yields]Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr[sub 64][yields]Ter and (2) utilization of a cryptic splice site for Gln[sub 310][yields]Ter. In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected. 28 refs., 4 figs., 3 tabs.
- OSTI ID:
- 5852683
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 53:2; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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