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.
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, Gly409-->Arg in exon 9 and Ter-->Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr64-->Ter), exon 7 (Gln310-->Ter), or exon 8 (Thr366-->Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr366-->Pro and Ter-->Cys, permitted the expression of only trace amounts of alpha-L-iduronidase activity, whereas Gly409-->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 Tyr64-->Ter and (2) utilization of a cryptic splice site for Gln310-->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.
Bach
G
G
Department of Human Genetics, Hadassah Medical Center, Jerusalem.
Moskowitz
S M
SM
Tieu
P T
PT
Matynia
A
A
Neufeld
E F
EF
D000483:Alleles; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005006:Ethnicity; D005260:Female; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D007557:Israel; D008297:Male; D008969:Molecular Sequence Data; D008059:Mucopolysaccharidosis I / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D016372:RNA, Antisense / Q000032:analysis; D013029:Space-Time Clustering
D016372:RNA, Antisense; D007068:Iduronidase