Abstract
There is a high incidence of Niemann-Pick type B disease in the Maghreb region of North Africa, which includes Morocco, Algeria and Tunisia. A hypothesis that there may well be a common, predominant mutant acid sphingomyelinase allele responsible for the type B phenotype in this population has been tested. A deletion of an arginine codon at amino acid residue 608 was found in one patient. The same mutation was also observed in another of our cases. An original screening procedure using 3′end digoxigenin-labeled allele-specific oligonucleotides and chemiluminescent detection was developed and used parallel to the conventional assay with 5′-end radiolabeled oligonucleotides. Of the 15 non-related, non-Jewish North African type B patients studied, 12 were homozygous and two compound heterozygous for this deletion (26 ΔR608 alleles/30 mutant alleles). Among type B patients from other geographic regions (France, UK, Italy, Czechoslovakia), this mutation was observed in only one of the 16 alleles studied. Our results indicate that deletion of arginine 608 in the acid sphingomyelinase gene is the highly prevalent mutation underlying Niemann-Pick type B disease in the population of Maghreb. A varying severity of the clinical and enzymatic expression within the non-neuronopathic phenotype has however been observed in patients homozygous for the mutation.
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Arpaia E, Dumbrille-Ross A, Maler T, Neote K, Tropak M, Troxel C, Stirling JS, Pitts JS, Bapat B, Lamhonwah AM, Mahuran DJ, Schuster SM, Clarke JTR, Lowden JA, Gravel RA (1988) Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature 333:85–86
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K (1987) Current protocols in molecular biol-ogy. Wiley-Interscience, New York, NY
Beaudet AL, Manchreck AA (1982) Metabolism of sphingomyelin by intact cultured fibroblasts: differentiation of Niemann-Pick disease types A and B. Biochem Biophys Res Commun 105:14–19
Ben Hamida M, Fardeau M, Attia N (1983) Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 6:469–480
Beutler E (1992) Gaucher disease: new molecular approaches to diagnosis and treatment. Science 256:794–799
Dos Santos MR, Tanaka A, Sá Miranda MC, Ribeiro MG, Maia M, Suzuki K (1991) GM2-gangliosidosis B1 variant: analysis of β-hexosaminidase α gene mutations in eleven patients from a defined region in Portugal. Am J Hum Genet 49:886–890
Elleder M, Cihula J (1983) Niemann-Pick disease (variation in the sphingomyelinase deficiency group). Neurovisceral phenotype (A) with an abnormally protracted clinical course and variable expression of neurological symptomatology in three siblings. Eur J Pediatr 140:323–328
Elleder M, Nevoral J, Spicacova V, Hynovia H, Kraus J, Krasny J, Vanier MT (1986) A new variant of sphingomyelinase deficiency (Niemann-Pick): visceromegaly, minimal neurological lesions and low in vitro degradation rate of sphingomyelin. J Inherited Metab Dis 9:357–366
Ferlinz K, Hurwitz R, Sandhoff K (1991) Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A. Biochem Biophys Res Commun 179:1187–1191
Kofman J, Chevalier JP, Baraton G, Brun J (1979) Maladie de Niemann-Pick révélée par une miliaire pulmonaire. Poumon 35:217–222
Kudoh T, Velkoff M, Wenger DA (1983) Uptake and metabolism of radioactively labeled sphingomyelin in cultured skin fibroblasts from controls and patients with Niemann-Pick disease and other lysosomal disease. Biochim Biophys Acta 754:82–92
Levran O, Desnick RJ, Schuchman EH (1991a) Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients. Proc Natl Acad Sci USA 88:3748–3752
Levran O, Desnick RJ, Schuchman EH (1991b) Niemann-Pick type B disease: identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients. J Clin Invest 88:806–810
Myerowitz R (1988) Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. Proc Natl Acad Sci USA 85:3955–3958
Myerowitz R, Costigan C (1988) The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the α-chain of β-hexosaminidase. J Biol Chem 263:18587–18589
Myerowitz R, Hogikyan ND (1986) Different mutations in Ashkenazi Jewish and non-Jewish French Canadians with Tay-Sachs disease. Science 232:1646–1648
Navon R (1991) Molecular and clinical heterogeneity of adult GM2 gangliosidosis. Dev Neurosci 13:295–298
Navon R, Proia RL (1989) The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay-Sachs disease. Science 243:1471–1474
Ohno K, Suzuki K (1988) A splicing defect due to an exon-intron junctional mutation results in abnormal β-hexosaminidase α chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. Biochem Biophys Res Commun 153:463–469
Quintern LE, Schuchman EH, Levran O, Suchi M, Ferlinz K, Reinke H, Sandhoff K, Desnick RJ (1989) Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts. EMBO J 8:2469–2473
Rodon P, Ramain JP, Bruandet P, Piedon J, Akli J, Penot J (1991) La maladie de Niemann-Pick type B avec syndrome des histiocytes bleu de mer. Rev Med Int 12:299–302
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ (1991) Human acid sphingomyelinase: isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem 66:8531–8539
Schuchman EH, Levran O, Pereira LV, Desnick RJ (1992) Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1). Genomics 12:197–205
Spence MW, Callahan JW (1989) Sphingomyelin-cholesterol lipidosis: the Niemann-Pick group of diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1655–1676
Suzuki K, Vanier MT (1991) Biochemical and molecular aspects of late-onset GM2-gangliosidosis: B1 variant as the prototype. Dev Neurosci 13:288–294
Takahashi T, Suchi M, Desnick RJ, Takada G, Schuchman EH (1992 a) Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms. J Biol Chem 267:12552–12558
Takahashi T, Desnick RJ, Takada G, Schuchman EH (1992b) Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease. Hum Mutat 1:70–71
Vanier MT (1983) Biochemical studies in Niemann-Pick disease I. Major sphingolipids of liver and spleen. Biochim Biophys Acta 750:178–184
Vanier MT, Revol A, Fichet M (1980) Sphingomyelinase activities of various human tissues in control subjects and in NiemannPick disease. Development and evaluation of a microprocedure. Clin Chim Acta 106:257–267
Vanier MT, Rousson R, Garcia I, Bailloud G, Juge M-C, Revol A, Louisot P (1985) Biochemical studies in Niemann-Pick disease. III. In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the disease. Clin Genet 27:20–32
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Vanier, M.T., Ferlinz, K., Rousson, R. et al. Deletion of arginine (608) in acid sphingomyelinase is the prevalent mutation among Niemann-Pick disease type B patients from northern Africa. Hum Genet 92, 325–330 (1993). https://doi.org/10.1007/BF01247328
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DOI: https://doi.org/10.1007/BF01247328