Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jan;64(1):77–88. doi: 10.1086/302183

Spectrum of mutations in alpha-mannosidosis.

T Berg 1, H M Riise 1, G M Hansen 1, D Malm 1, L Tranebjaerg 1, O K Tollersrud 1, O Nilssen 1
PMCID: PMC1377705  PMID: 9915946

Abstract

alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first alpha-mannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident.

Full Text

The Full Text of this article is available as a PDF (256.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1–3. doi: 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  2. Aronson N. N., Jr, Kuranda M. J. Lysosomal degradation of Asn-linked glycoproteins. FASEB J. 1989 Dec;3(14):2615–2622. doi: 10.1096/fasebj.3.14.2531691. [DOI] [PubMed] [Google Scholar]
  3. Autio S., Nordén N. E., Ockerman P. A., Riekkinen P., Rapola J., Louhimo T. Mannosidosis: clinical, fine-structural and biochemical findings in three cases. Acta Paediatr Scand. 1973 Nov;62(6):555–565. doi: 10.1111/j.1651-2227.1973.tb17065.x. [DOI] [PubMed] [Google Scholar]
  4. Aylsworth A. S., Taylor H. A., Stuart C. M., Thomas G. H. Mannosidosis: phenotype of a severely affected child and characterization of alpha-mannosidase activity in cultured fibroblasts from the patient and his parents. J Pediatr. 1976 May;88(5):814–818. doi: 10.1016/s0022-3476(76)81120-1. [DOI] [PubMed] [Google Scholar]
  5. Bach G., Kohn G., Lasch E. E., El Massri M., Ornoy A., Sekeles E., Legum C., Cohen M. M. A new variant of mannosidosis with increased residual enzymatic activity and mild clinical manifestation. Pediatr Res. 1978 Oct;12(10):1010–1015. doi: 10.1203/00006450-197810000-00012. [DOI] [PubMed] [Google Scholar]
  6. Beccari T., Appolloni M. G., Costanzi E., Stinchi S., Stirling J. L., Della Fazia M. A., Servillo G., Viola M. P., Orlacchio A. Lysosomal alpha-mannosidases of mouse tissues: characteristics of the isoenzymes, and cloning and expression of a full-length cDNA. Biochem J. 1997 Oct 1;327(Pt 1):45–49. doi: 10.1042/bj3270045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bennet J. K., Dembure P. P., Elsas L. J. Clinical and biochemical analysis of two families with type I and type II mannosidosis. Am J Med Genet. 1995 Jan 2;55(1):21–26. doi: 10.1002/ajmg.1320550108. [DOI] [PubMed] [Google Scholar]
  8. Berg T., Healy P. J., Tollersrud O. K., Nilssen O. Molecular heterogeneity for bovine alpha-mannosidosis: PCR based assays for detection of breed-specific mutations. Res Vet Sci. 1997 Nov-Dec;63(3):279–282. doi: 10.1016/s0034-5288(97)90034-5. [DOI] [PubMed] [Google Scholar]
  9. Berg T., Tollersrud O. K., Walkley S. U., Siegel D., Nilssen O. Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats. Biochem J. 1997 Dec 15;328(Pt 3):863–870. doi: 10.1042/bj3280863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Burditt L. J., Chotai K. A., Winchester B. G. Evidence that the mutant enzyme in fibroblasts of a patient with mannosidosis does not crossreact with antiserum raised against normal acidic alpha-D-mannosidase. FEBS Lett. 1978 Jul 15;91(2):186–189. doi: 10.1016/0014-5793(78)81168-5. [DOI] [PubMed] [Google Scholar]
  11. Burditt L. J., Chotai K., Hirani S., Nugent P. G., Winchester B. G., Blakemore W. F. Biochemical studies on a case of feline mannosidosis. Biochem J. 1980 Sep 1;189(3):467–473. doi: 10.1042/bj1890467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cerruti Mainardi P., Gatti R., Javarone A., Filocamo M., Levis F., Borrone C. La mannosidosi. Studio di due famiglie e diagnosi prenatale. Pediatr Med Chir. 1982 May-Jun;4(3):203–214. [PubMed] [Google Scholar]
  13. Cooper D. N., Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. doi: 10.1007/BF00278187. [DOI] [PubMed] [Google Scholar]
  14. Farriaux J. P., Legouis I., Humbel R., Dhondt J. L., Richard P., Strecker G., Fourmaintraux A., Ringel J., Fontaine G. La mannosidose. A propos de 5 observations. Nouv Presse Med. 1975 Jun 21;4(25):1867–1870. [PubMed] [Google Scholar]
  15. Gehler J., Cantz M., O'Brien J. F., Tolksdorf M., Spranger J. Mannosidosis: clinical and biochemical findings. Birth Defects Orig Artic Ser. 1975;11(6):269–272. [PubMed] [Google Scholar]
  16. Gotoda Y., Wakamatsu N., Kawai H., Nishida Y., Matsumoto T. Missense and nonsense mutations in the lysosomal alpha-mannosidase gene (MANB) in severe and mild forms of alpha-mannosidosis. Am J Hum Genet. 1998 Oct;63(4):1015–1024. doi: 10.1086/302048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grard T., Herman V., Saint-Pol A., Kmiecik D., Labiau O., Mir A. M., Alonso C., Verbert A., Cacan R., Michalski J. C. Oligomannosides or oligosaccharide-lipids as potential substrates for rat liver cytosolic alpha-D-mannosidase. Biochem J. 1996 Jun 15;316(Pt 3):787–792. doi: 10.1042/bj3160787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hocking J. D., Jolly R. D., Batt R. D. Deficiency of alpha-mannosidase in Angus cattle. An inherited lysosomal storage disease. Biochem J. 1972 Jun;128(1):69–78. doi: 10.1042/bj1280069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jackson I. J. A reappraisal of non-consensus mRNA splice sites. Nucleic Acids Res. 1991 Jul 25;19(14):3795–3798. doi: 10.1093/nar/19.14.3795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jansen P. H., Schoonderwaldt H. C., Renier W. O., Wevers R. A., Gabreëls F. J. Mannosidosis: a study of two patients, presenting clinical heterogeneity. Clin Neurol Neurosurg. 1987;89(3):185–192. doi: 10.1016/s0303-8467(87)80053-7. [DOI] [PubMed] [Google Scholar]
  21. Kaneda Y., Hayes H., Uchida T., Yoshida M. C., Okada Y. Regional assignment of five genes on human chromosome 19. Chromosoma. 1987;95(1):8–12. doi: 10.1007/BF00293835. [DOI] [PubMed] [Google Scholar]
  22. Liao Y. F., Lal A., Moremen K. W. Cloning, expression, purification, and characterization of the human broad specificity lysosomal acid alpha-mannosidase. J Biol Chem. 1996 Nov 8;271(45):28348–28358. doi: 10.1074/jbc.271.45.28348. [DOI] [PubMed] [Google Scholar]
  23. Loeb H., Tondeur M., Toppet M., Cremer N. Clinical, biochemical and ultrastructural studies of an atypical form of mucopolysaccharidosis. Acta Paediatr Scand. 1969 May;58(3):220–228. doi: 10.1111/j.1651-2227.1969.tb04710.x. [DOI] [PubMed] [Google Scholar]
  24. Malm D., Tollersrud O. K., Tranebjaerg L., Månsson J. E. Alfamannosidose. Tidsskr Nor Laegeforen. 1995 Feb 20;115(5):594–597. [PubMed] [Google Scholar]
  25. Mersmann G., Buddecke E. Evidence for material from mannosidosis fibroblasts crossreacting with anti-acidic alpha-mannosidase antibodies. FEBS Lett. 1977 Jan 15;73(1):123–126. [PubMed] [Google Scholar]
  26. Michelakakis H., Dimitriou E., Mylona-Karayanni C., Bartsocas C. S. Phenotypic variability of mannosidosis type II: report of two Greek siblings. Genet Couns. 1992;3(4):195–199. [PubMed] [Google Scholar]
  27. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mitchell M. L., Erickson R. P., Schmid D., Hieber V., Poznanski A. K., Hicks S. P. Mannosidosis: two brothers with different degrees of disease severity. Clin Genet. 1981 Sep;20(3):191–202. doi: 10.1111/j.1399-0004.1981.tb01829.x. [DOI] [PubMed] [Google Scholar]
  29. Moremen K. W., Robbins P. W. Isolation, characterization, and expression of cDNAs encoding murine alpha-mannosidase II, a Golgi enzyme that controls conversion of high mannose to complex N-glycans. J Cell Biol. 1991 Dec;115(6):1521–1534. doi: 10.1083/jcb.115.6.1521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nebes V. L., Schmidt M. C. Human lysosomal alpha-mannosidase: isolation and nucleotide sequence of the full-length cDNA. Biochem Biophys Res Commun. 1994 Apr 15;200(1):239–245. doi: 10.1006/bbrc.1994.1440. [DOI] [PubMed] [Google Scholar]
  31. Nilssen O., Berg T., Riise H. M., Ramachandran U., Evjen G., Hansen G. M., Malm D., Tranebjaerg L., Tollersrud O. K. alpha-Mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet. 1997 May;6(5):717–726. doi: 10.1093/hmg/6.5.717. [DOI] [PubMed] [Google Scholar]
  32. Nilssen O., Tollersrud O. K., Borud O., Tranebjaerg L. A simple and rapid PCR based method for AGU(Fin) determination. Hum Mol Genet. 1993 Apr;2(4):484–484. doi: 10.1093/hmg/2.4.484. [DOI] [PubMed] [Google Scholar]
  33. Padgett R. A., Grabowski P. J., Konarska M. M., Seiler S., Sharp P. A. Splicing of messenger RNA precursors. Annu Rev Biochem. 1986;55:1119–1150. doi: 10.1146/annurev.bi.55.070186.005351. [DOI] [PubMed] [Google Scholar]
  34. Park H., Fisher K. J., Aronson N. N., Jr Genomic structure of human lysosomal glycosylasparaginase. FEBS Lett. 1991 Aug 19;288(1-2):168–172. doi: 10.1016/0014-5793(91)81027-6. [DOI] [PubMed] [Google Scholar]
  35. Patton M. A., Barnes I. C., Young I. D., Harper P. S., Pennock C. A. Mannosidosis in two brothers: prolonged survival in the severe phenotype. Clin Genet. 1982 Nov;22(5):284–289. doi: 10.1111/j.1399-0004.1982.tb01447.x. [DOI] [PubMed] [Google Scholar]
  36. Poenaru L., Miranda C., Dreyfus J. C. Residual mannosidase activity in human mannosidosis: characterization of the mutant enzyme. Am J Hum Genet. 1980 May;32(3):354–363. [PMC free article] [PubMed] [Google Scholar]
  37. Pohlmann R., Hasilik A., Cheng S., Pemble S., Winchester B., von Figura K. Synthesis of lysosomal alpha-mannosidase in normal and mannosidosis fibroblasts. Biochem Biophys Res Commun. 1983 Sep 30;115(3):1083–1089. doi: 10.1016/s0006-291x(83)80046-1. [DOI] [PubMed] [Google Scholar]
  38. Riise H. M., Berg T., Nilssen O., Romeo G., Tollersrud O. K., Ceccherini I. Genomic structure of the human lysosomal alpha-mannosidase gene (MANB). Genomics. 1997 Jun 1;42(2):200–207. doi: 10.1006/geno.1997.4668. [DOI] [PubMed] [Google Scholar]
  39. Spranger J., Gehler J., Cantz M. The radiographic features of mannosidosis. Radiology. 1976 May;119(2):401–407. doi: 10.1148/119.2.401. [DOI] [PubMed] [Google Scholar]
  40. Tollersrud O. K., Berg T., Healy P., Evjen G., Ramachandran U., Nilssen O. Purification of bovine lysosomal alpha-mannosidase, characterization of its gene and determination of two mutations that cause alpha-mannosidosis. Eur J Biochem. 1997 Jun 1;246(2):410–419. doi: 10.1111/j.1432-1033.1997.00410.x. [DOI] [PubMed] [Google Scholar]
  41. Warner T. G., Mock A. K., Nyhan W. L., O'Brien J. S. Alpha-mannosidosis: analysis of urinary oligosaccharides with high performance liquid chromatography and diagnosis of a case with unusually mild presentation. Clin Genet. 1984 Mar;25(3):248–255. doi: 10.1111/j.1399-0004.1984.tb01985.x. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES