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
G. Bach et al., 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, American journal of human genetics, 53(2), 1993, pp. 330-338
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 sequenci
ng of PCR products, and (c) restriction-enzyme analysis. One allele ha
s two amino acid substitutions, Gly409-->Arg in exon 9 and Ter-->Cys i
n exon 14. The other three alleles have mutations in exon 2 (Tyr64-->T
er), 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 am
ounts Of alpha-L-iduronidase activity, whereas Gly409-->Arg permitted
the expression of 60% as much enzyme as did the normal cDNA. The nonse
nse 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 hetero
zygous, for the mutant alleles, as anticipated from the consanguinity
in each family. The two-mutation allele was identified in a family fro
m Gaza; the other three alleles were found in seven families, five of
them Druze, residing in a very small area of northern Israel. Since su
ch clustering suggests a classic founder effect, the presence of three
mutant alleles of the IDUA gene was unexpected.