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. 1995 Jan;56(1):51–57.

Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area.

U Heinisch 1, J Zlotogora 1, S Kafert 1, V Gieselmann 1
PMCID: PMC1801341  PMID: 7825603

Abstract

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. The disease occurs panethnically, with an estimated frequency of 1/40,000. Metachromatic leukodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel. Ten families with affected children have been found, three in the Jerusalem region and seven in a small area in lower Galilee. Whereas all patients from the Jerusalem region are homozygous for a frequent mutant arylsulfatase A allele, five different mutations were found in the families from lower Galilee. In patients of Muslim Arab origin, we have found a G86-->D, a S96-->L, and a Q190-->H substitution. Two different defective arylsulfatase A alleles, characterized by a T274-->M and a R370-->W substitution, respectively, have been found among the Christian Arab patients. All mutations were introduced into the wild-type arylsulfatase A cDNA. No enzyme activity could be expressed from the mutagenized cDNAs after transfection into heterologous cells. In all instances, the patients were found to be homozygous for the mutations, and four of the five mutations occurred on different haplotypes. The clustering of this rare lysosomal storage disease in a small geographic area usually suggests a founder effect, so the finding of five different mutations is surprising.

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Selected References

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  1. Artelt P., Morelle C., Ausmeier M., Fitzek M., Hauser H. Vectors for efficient expression in mammalian fibroblastoid, myeloid and lymphoid cells via transfection or infection. Gene. 1988 Sep 7;68(2):213–219. doi: 10.1016/0378-1119(88)90023-6. [DOI] [PubMed] [Google Scholar]
  2. Bach G., Moskowitz S. M., Tieu P. T., Matynia A., Neufeld E. F. 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. Am J Hum Genet. 1993 Aug;53(2):330–338. [PMC free article] [PubMed] [Google Scholar]
  3. Barth M. L., Fensom A., Harris A. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum Genet. 1993 Mar;91(1):73–77. doi: 10.1007/BF00230227. [DOI] [PubMed] [Google Scholar]
  4. Diamond J. M., Rotter J. I. Observing the founder effect in human evolution. Nature. 1987 Sep 10;329(6135):105–106. doi: 10.1038/329105a0. [DOI] [PubMed] [Google Scholar]
  5. Flint J., Harding R. M., Clegg J. B., Boyce A. J. Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants. Hum Genet. 1993 Mar;91(2):91–117. doi: 10.1007/BF00222709. [DOI] [PubMed] [Google Scholar]
  6. Freundlich E., Hino N. Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci. 1984 Nov;20(11):1035–1038. [PubMed] [Google Scholar]
  7. Gieselmann V., Polten A., Kreysing J., von Figura K. Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9436–9440. doi: 10.1073/pnas.86.23.9436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gustavson K. H., Hagberg B. The incidence and genetics of metachromatic leucodystrophy in northern Sweden. Acta Paediatr Scand. 1971 Sep;60(5):585–590. doi: 10.1111/j.1651-2227.1971.tb06994.x. [DOI] [PubMed] [Google Scholar]
  9. Harvey J. S., Nelson P. V., Carey W. F., Robertson E. F., Morris C. P. An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy. Hum Mutat. 1993;2(4):261–267. doi: 10.1002/humu.1380020405. [DOI] [PubMed] [Google Scholar]
  10. Hechtman P., Boulay B., De Braekeleer M., Andermann E., Melançon S., Larochelle J., Prevost C., Kaplan F. The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada. Hum Genet. 1992 Dec;90(4):402–406. doi: 10.1007/BF00220467. [DOI] [PubMed] [Google Scholar]
  11. Hechtman P., Kaplan F., Bayleran J., Boulay B., Andermann E., de Braekeleer M., Melançon S., Lambert M., Potier M., Gagné R. More than one mutant allele causes infantile Tay-Sachs disease in French-Canadians. Am J Hum Genet. 1990 Nov;47(5):815–822. [PMC free article] [PubMed] [Google Scholar]
  12. Jaber L., Merlob P., Bu X., Rotter J. I., Shohat M. Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community. Am J Med Genet. 1992 Sep 1;44(1):1–6. doi: 10.1002/ajmg.1320440102. [DOI] [PubMed] [Google Scholar]
  13. Kreysing J., von Figura K., Gieselmann V. Structure of the arylsulfatase A gene. Eur J Biochem. 1990 Aug 17;191(3):627–631. doi: 10.1111/j.1432-1033.1990.tb19167.x. [DOI] [PubMed] [Google Scholar]
  14. Nakamaye K. L., Eckstein F. Inhibition of restriction endonuclease Nci I cleavage by phosphorothioate groups and its application to oligonucleotide-directed mutagenesis. Nucleic Acids Res. 1986 Dec 22;14(24):9679–9698. doi: 10.1093/nar/14.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Polten A., Fluharty A. L., Fluharty C. B., Kappler J., von Figura K., Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 1991 Jan 3;324(1):18–22. doi: 10.1056/NEJM199101033240104. [DOI] [PubMed] [Google Scholar]
  16. Stein C., Gieselmann V., Kreysing J., Schmidt B., Pohlmann R., Waheed A., Meyer H. E., O'Brien J. S., von Figura K. Cloning and expression of human arylsulfatase A. J Biol Chem. 1989 Jan 15;264(2):1252–1259. [PubMed] [Google Scholar]
  17. Zlotogora J. Is the presence of two different Tay-Sachs disease mutations in a Cajun population an unexpected observation? Am J Hum Genet. 1993 May;52(5):1014–1016. [PMC free article] [PubMed] [Google Scholar]
  18. Zlotogora J., Levy-Lahad E., Legum C., Iancu T. C., Zeigler M., Bach G. Krabbe disease in Israel. Isr J Med Sci. 1991 Apr;27(4):196–198. [PubMed] [Google Scholar]
  19. Zlotogora J., Zeigler M., Bach G. Selection in favor of lysosomal storage disorders? Am J Hum Genet. 1988 Feb;42(2):271–273. [PMC free article] [PubMed] [Google Scholar]

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