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. 1997 Jun;34(6):470–475. doi: 10.1136/jmg.34.6.470

Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D).

A Carrié 1, F Piccolo 1, F Leturcq 1, C de Toma 1, K Azibi 1, C Beldjord 1, J M Vallat 1, L Merlini 1, T Voit 1, C Sewry 1, J A Urtizberea 1, N Romero 1, F M Tomé 1, M Fardeau 1, Y Sunada 1, K P Campbell 1, J C Kaplan 1, M Jeanpierre 1
PMCID: PMC1050969  PMID: 9192266

Abstract

Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies in which the primary defect may reside in any of the genes coding for the different partners of the sarcolemmal sarcoglycan (SG) complex: the alpha-SG (LGMD2D at 17q21.2), the beta-SG (LGMD2E at 4q12), the gamma-SG (LGMD2C at 13q12), and the delta-SG (LGMD2F at 5q33). We report a series of 20 new unrelated families with 14 different mutations in the alpha-SG gene. Along with the mutations that we previously reported this brings our cohort of patients with alpha-sarcoglycanopathy to a total of 31 unrelated patients, carrying 25 different mutations. The missense mutations reside in the extracellular domain of the protein. Five of 15 missense mutations, carried by unrelated subjects on different haplotype backgrounds and of widespread geographical origins, account for 58% of the mutated chromosomes, with a striking prevalence of the R77C substitution (32%). The severity of the disease varies strikingly and correlates at least in part with the amount of residual protein and the type of mutation. The recurrent R284C substitution is associated with a benign disease course.

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Selected References

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

  1. Azibi K., Bachner L., Beckmann J. S., Matsumura K., Hamouda E., Chaouch M., Chaouch A., Ait-Ouarab R., Vignal A., Weissenbach J. Severe childhood autosomal recessive muscular dystrophy with the deficiency of the 50 kDa dystrophin-associated glycoprotein maps to chromosome 13q12. Hum Mol Genet. 1993 Sep;2(9):1423–1428. doi: 10.1093/hmg/2.9.1423. [DOI] [PubMed] [Google Scholar]
  2. Ben Hamida M., Fardeau M., Attia N. Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve. 1983 Sep;6(7):469–480. doi: 10.1002/mus.880060702. [DOI] [PubMed] [Google Scholar]
  3. Ben Othmane K., Ben Hamida M., Pericak-Vance M. A., Ben Hamida C., Blel S., Carter S. C., Bowcock A. M., Petruhkin K., Gilliam T. C., Roses A. D. Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nat Genet. 1992 Dec;2(4):315–317. doi: 10.1038/ng1292-315. [DOI] [PubMed] [Google Scholar]
  4. Bushby K. M., Beckmann J. S. The limb-girdle muscular dystrophies--proposal for a new nomenclature. Neuromuscul Disord. 1995 Jul;5(4):337–343. doi: 10.1016/0960-8966(95)00005-8. [DOI] [PubMed] [Google Scholar]
  5. Bönnemann C. G., Modi R., Noguchi S., Mizuno Y., Yoshida M., Gussoni E., McNally E. M., Duggan D. J., Angelini C., Hoffman E. P. Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nat Genet. 1995 Nov;11(3):266–273. doi: 10.1038/ng1195-266. [DOI] [PubMed] [Google Scholar]
  6. Campbell K. P. Adhalin gene mutations and autosomal recessive limb-girdle muscular dystrophy. Ann Neurol. 1995 Sep;38(3):353–354. doi: 10.1002/ana.410380302. [DOI] [PubMed] [Google Scholar]
  7. Ervasti J. M., Campbell K. P. Membrane organization of the dystrophin-glycoprotein complex. Cell. 1991 Sep 20;66(6):1121–1131. doi: 10.1016/0092-8674(91)90035-w. [DOI] [PubMed] [Google Scholar]
  8. Fardeau M., Matsumura K., Tomé F. M., Collin H., Leturcq F., Kaplan J. C., Campbell K. P. Deficiency of the 50 kDa dystrophin associated glycoprotein (adhalin) in severe autosomal recessive muscular dystrophies in children native from European countries. C R Acad Sci III. 1993 Aug;316(8):799–804. [PubMed] [Google Scholar]
  9. Fernandez E., Bienvenu T., Desclaux Arramond F., Beldjord K., Kaplan J. C., Beldjord C. Use of chemical clamps in denaturing gradient gel electrophoresis: application in the detection of the most frequent Mediterranean beta-thalassemic mutations. PCR Methods Appl. 1993 Oct;3(2):122–124. doi: 10.1101/gr.3.2.122. [DOI] [PubMed] [Google Scholar]
  10. Giannelli F., Green P. M., Sommer S. S., Lillicrap D. P., Ludwig M., Schwaab R., Reitsma P. H., Goossens M., Yoshioka A., Brownlee G. G. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534–3546. doi: 10.1093/nar/22.17.3534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kawai H., Akaike M., Endo T., Adachi K., Inui T., Mitsui T., Kashiwagi S., Fujiwara T., Okuno S., Shin S. Adhalin gene mutations in patients with autosomal recessive childhood onset muscular dystrophy with adhalin deficiency. J Clin Invest. 1995 Sep;96(3):1202–1207. doi: 10.1172/JCI118152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lerman L. S., Silverstein K. Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:482–501. doi: 10.1016/0076-6879(87)55032-7. [DOI] [PubMed] [Google Scholar]
  13. Lim L. E., Duclos F., Broux O., Bourg N., Sunada Y., Allamand V., Meyer J., Richard I., Moomaw C., Slaughter C. Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet. 1995 Nov;11(3):257–265. doi: 10.1038/ng1195-257. [DOI] [PubMed] [Google Scholar]
  14. Ljunggren A., Duggan D., McNally E., Boylan K. B., Gama C. H., Kunkel L. M., Hoffman E. P. Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin. Ann Neurol. 1995 Sep;38(3):367–372. doi: 10.1002/ana.410380305. [DOI] [PubMed] [Google Scholar]
  15. Matsumura K., Tomé F. M., Collin H., Azibi K., Chaouch M., Kaplan J. C., Fardeau M., Campbell K. P. Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. Nature. 1992 Sep 24;359(6393):320–322. doi: 10.1038/359320a0. [DOI] [PubMed] [Google Scholar]
  16. McNally E. M., Yoshida M., Mizuno Y., Ozawa E., Kunkel L. M. Human adhalin is alternatively spliced and the gene is located on chromosome 17q21. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9690–9694. doi: 10.1073/pnas.91.21.9690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nigro V., de Sá Moreira E., Piluso G., Vainzof M., Belsito A., Politano L., Puca A. A., Passos-Bueno M. R., Zatz M. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nat Genet. 1996 Oct;14(2):195–198. doi: 10.1038/ng1096-195. [DOI] [PubMed] [Google Scholar]
  18. Passos-Bueno M. R., Oliveira J. R., Bakker E., Anderson R. D., Marie S. K., Vainzof M., Roberds S., Campbell K. P., Zatz M. Genetic heterogeneity for Duchenne-like muscular dystrophy (DLMD) based on linkage and 50 DAG analysis. Hum Mol Genet. 1993 Nov;2(11):1945–1947. doi: 10.1093/hmg/2.11.1945. [DOI] [PubMed] [Google Scholar]
  19. Piccolo F., Roberds S. L., Jeanpierre M., Leturcq F., Azibi K., Beldjord C., Carrié A., Récan D., Chaouch M., Reghis A. Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. Nat Genet. 1995 Jun;10(2):243–245. doi: 10.1038/ng0695-243. [DOI] [PubMed] [Google Scholar]
  20. Roberds S. L., Anderson R. D., Ibraghimov-Beskrovnaya O., Campbell K. P. Primary structure and muscle-specific expression of the 50-kDa dystrophin-associated glycoprotein (adhalin). J Biol Chem. 1993 Nov 15;268(32):23739–23742. [PubMed] [Google Scholar]
  21. Roberds S. L., Leturcq F., Allamand V., Piccolo F., Jeanpierre M., Anderson R. D., Lim L. E., Lee J. C., Tomé F. M., Romero N. B. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell. 1994 Aug 26;78(4):625–633. doi: 10.1016/0092-8674(94)90527-4. [DOI] [PubMed] [Google Scholar]
  22. Romero N. B., Tomé F. M., Leturcq F., el Kerch F. E., Azibi K., Bachner L., Anderson R. D., Roberds S. L., Campbell K. P., Fardeau M. Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDa dystrophin-associated glycoprotein) deficiency. C R Acad Sci III. 1994 Jan;317(1):70–76. [PubMed] [Google Scholar]
  23. Sapienza C. A paternal wash in Apert syndrome. Nat Genet. 1996 May;13(1):9–10. doi: 10.1038/ng0596-9. [DOI] [PubMed] [Google Scholar]
  24. Tornaletti S., Pfeifer G. P. Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene. 1995 Apr 20;10(8):1493–1499. [PubMed] [Google Scholar]
  25. Wacey A. I., Kemball-Cook G., Kazazian H. H., Antonarakis S. E., Schwaab R., Lindley P., Tuddenham E. G. The haemophilia A mutation search test and resource site, home page of the factor VIII mutation database: HAMSTeRS. Nucleic Acids Res. 1996 Jan 1;24(1):100–102. doi: 10.1093/nar/24.1.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Watkins H., Seidman J. G., Seidman C. E. Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. Hum Mol Genet. 1995;4(Spec No):1721–1727. doi: 10.1093/hmg/4.suppl_1.1721. [DOI] [PubMed] [Google Scholar]
  27. Yamamoto H., Hagiwara Y., Mizuno Y., Yoshida M., Ozawa E. Heterogeneity of dystrophin-associated proteins. J Biochem. 1993 Jul;114(1):132–139. doi: 10.1093/oxfordjournals.jbchem.a124128. [DOI] [PubMed] [Google Scholar]
  28. el Kerch F., Sefiani A., Azibi K., Boutaleb N., Yahyaoui M., Bentahila A., Vinet M. C., Leturcq F., Bachner L., Beckmann J. Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in north Africa. J Med Genet. 1994 Apr;31(4):342–343. doi: 10.1136/jmg.31.4.342. [DOI] [PMC free article] [PubMed] [Google Scholar]

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