Evolutionary relationship and ethnic variations of two tightly linked mutations in the gene coding for the lysosomal enzyme arylsulfatase
- McMaster Univ., Ontario (Canada)
Metachromatic leukodystrophy is a neurodegenerative disease caused by deficiency of the lysosomal enzyme arylsulfatase A. However, some individuals with deficient enzyme activity appear phenotypically normal. This pseudodeficiency (PD) state is associated with two A{r_arrow}G transitions causing the loss of an N-glycosylation site in exon 6 and a polyadenylation signal at the 3{prime} end. To understand the evolutionary basis for this unusually tight linkage, we compared the occurrence of these two mutations among selected ethnic groups singly or together and their haplotype backgrounds. From 100 unrelated individuals from each of the Black, Caucasian, East Indian and Oriental populations, we found no individual carrying the polyadenylation mutation alone. However, the N-glycosylation mutation occurred independently in all the populations. RFLP analysis among random individuals revealed 7 enzyme polymorphisms (Bam II, Bgl I, Bgl II, Bsr I, Hind III, Pvu II and Taq I). Haplotype analysis among homozygous individuals and 9 multi-generation families showed that of the 7 polymorphisms, one (Bsr I) appeared indiscriminately throughout all the haplotypes studied and did not contribute to the analysis. Haplotypes established from the 6 remaining polymorphisms showed that all the alleles carrying both mutations have the same haplotype in different ethnic groups but may differ at the Bgl II and Taq I sites from those carrying only the N-glycosylation mutation. Hence, the extreme linkage disequilibrium between the two mutations associated with PD was established before the divergence of the races and the variations in frequencies are likely due to population genetic drift. Furthermore, the N-glycosylation mutation that occurs alone may appear on different haplotype backgrounds and hence is not necessarily the predecessor to the tightly-linked polyadenylation mutations in PD.
- OSTI ID:
- 133924
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0658
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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