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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1996 Oct;59(4):872–878.

Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.

T Weiler 1, C R Greenberg 1, E Nylen 1, W Halliday 1, K Morgan 1, D Eggertson 1, K Wrogemann 1
PMCID: PMC1914810  PMID: 8808603

Abstract

We report the results of our investigations of a large, inbred, aboriginal Canadian kindred with nine muscular dystrophy patients. The ancestry of all but two of the carrier parents could be traced to a founder couple, seven generations back. Seven patients presented with proximal myopathy consistent with limb girdle-type muscular dystrophy (LGMD), whereas two patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy (distal autosomal recessive muscular dystrophy) (MM). Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MM is consistent with autosomal recessive inheritance, and the putative locus is significantly linked (LOD scores >3.0) to six marker loci that span the region of the LGMD2B locus on chromosome 2p. Our initial hypothesis that the affected patients would all be homozygous by descent for microsatellite markers surrounding the disease locus was rejected. Rather, two different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating that there are two mutant alleles of independent origin in this kindred. There was no association, however, between the two different haplotypes and clinical variability; they do not distinguish between the LGMD and MM phenotypes. Thus, we conclude that LGMD and MM in our population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must contribute to the clinical phenotype.

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Selected References

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  1. Allamand V., Broux O., Richard I., Fougerousse F., Chiannilkulchai N., Bourg N., Brenguier L., Devaud C., Pasturaud P., Pereira de Souza A. Preferential localization of the limb-girdle muscular dystrophy type 2A gene in the proximal part of a 1-cM 15q15.1-q15.3 interval. Am J Hum Genet. 1995 Jun;56(6):1417–1430. [PMC free article] [PubMed] [Google Scholar]
  2. Bashir R., Strachan T., Keers S., Stephenson A., Mahjneh I., Marconi G., Nashef L., Bushby K. M. A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. Hum Mol Genet. 1994 Mar;3(3):455–457. doi: 10.1093/hmg/3.3.455. [DOI] [PubMed] [Google Scholar]
  3. Bejaoui K., Hirabayashi K., Hentati F., Haines J. L., Ben Hamida C., Belal S., Miller R. G., McKenna-Yasek D., Weissenbach J., Rowland L. P. Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14. Neurology. 1995 Apr;45(4):768–772. doi: 10.1212/wnl.45.4.768. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Ben Othmane K., Speer M. C., Stauffer J., Blel S., Middleton L., Ben Hamida C., Etribi A., Loeb D., Hentati F., Roses A. D. Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy (LGMD2C) Am J Hum Genet. 1995 Sep;57(3):732–734. [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Bushby K. M. Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC Consortium on Limb-Girdle Dystrophies. Neuromuscul Disord. 1995 Jan;5(1):71–74. doi: 10.1016/0960-8966(93)e0006-g. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Cottingham R. W., Jr, Idury R. M., Schäffer A. A. Faster sequential genetic linkage computations. Am J Hum Genet. 1993 Jul;53(1):252–263. [PMC free article] [PubMed] [Google Scholar]
  10. Greenberg C. R., Hamerton J. L., Nigli M., Wrogemann K. DNA studies in a family with Duchenne muscular dystrophy and a deletion at Xp21. Am J Hum Genet. 1987 Aug;41(2):128–137. [PMC free article] [PubMed] [Google Scholar]
  11. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  12. Hillaire D., Leclerc A., Fauré S., Topaloglu H., Chiannilkulchaï N., Guicheney P., Grinas L., Legos P., Philpot J., Evangelista T. Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet. 1994 Sep;3(9):1657–1661. doi: 10.1093/hmg/3.9.1657. [DOI] [PubMed] [Google Scholar]
  13. Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. doi: 10.1038/ng1192-204. [DOI] [PubMed] [Google Scholar]
  14. Laing N. G., Laing B. A., Meredith C., Wilton S. D., Robbins P., Honeyman K., Dorosz S., Kozman H., Mastaglia F. L., Kakulas B. A. Autosomal dominant distal myopathy: linkage to chromosome 14. Am J Hum Genet. 1995 Feb;56(2):422–427. [PMC free article] [PubMed] [Google Scholar]
  15. Lander E. S., Botstein D. Mapping complex genetic traits in humans: new methods using a complete RFLP linkage map. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):49–62. doi: 10.1101/sqb.1986.051.01.007. [DOI] [PubMed] [Google Scholar]
  16. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  17. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lathrop G. M., Lalouel J. M., White R. L. Construction of human linkage maps: likelihood calculations for multilocus linkage analysis. Genet Epidemiol. 1986;3(1):39–52. doi: 10.1002/gepi.1370030105. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Noguchi S., McNally E. M., Ben Othmane K., Hagiwara Y., Mizuno Y., Yoshida M., Yamamoto H., Bönnemann C. G., Gussoni E., Denton P. H. Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science. 1995 Nov 3;270(5237):819–822. doi: 10.1126/science.270.5237.819. [DOI] [PubMed] [Google Scholar]
  21. Passos-Bueno M. R., Bashir R., Moreira E. S., Vainzof M., Marie S. K., Vasquez L., Iughetti P., Bakker E., Keers S., Stephenson A. Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region. Genomics. 1995 May 1;27(1):192–195. doi: 10.1006/geno.1995.1024. [DOI] [PubMed] [Google Scholar]
  22. Richard I., Broux O., Allamand V., Fougerousse F., Chiannilkulchai N., Bourg N., Brenguier L., Devaud C., Pasturaud P., Roudaut C. Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell. 1995 Apr 7;81(1):27–40. doi: 10.1016/0092-8674(95)90368-2. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Rodius F., Duclos F., Wrogemann K., Le Paslier D., Ougen P., Billault A., Belal S., Musenger C., Brice A., Dürr A. Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval. Am J Hum Genet. 1994 Jun;54(6):1050–1059. [PMC free article] [PubMed] [Google Scholar]
  25. Schäffer A. A. Faster linkage analysis computations for pedigrees with loops or unused alleles. Hum Hered. 1996 Jul-Aug;46(4):226–235. doi: 10.1159/000154358. [DOI] [PubMed] [Google Scholar]
  26. Schäffer A. A., Gupta S. K., Shriram K., Cottingham R. W., Jr Avoiding recomputation in linkage analysis. Hum Hered. 1994 Jul-Aug;44(4):225–237. doi: 10.1159/000154222. [DOI] [PubMed] [Google Scholar]
  27. Sirugo G., Keats B., Fujita R., Duclos F., Purohit K., Koenig M., Mandel J. L. Friedreich ataxia in Louisiana Acadians: demonstration of a founder effect by analysis of microsatellite-generated extended haplotypes. Am J Hum Genet. 1992 Mar;50(3):559–566. [PMC free article] [PubMed] [Google Scholar]
  28. Speer M. C., Gilchrist J. M., Chutkow J. G., McMichael R., Westbrook C. A., Stajich J. M., Jorgenson E. M., Gaskell P. C., Rosi B. L., Ramesar R. Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy. Am J Hum Genet. 1995 Dec;57(6):1371–1376. [PMC free article] [PubMed] [Google Scholar]
  29. Speer M. C., Yamaoka L. H., Gilchrist J. H., Gaskell C. P., Stajich J. M., Vance J. M., Kazantsev A., Lastra A. A., Haynes C. S., Beckmann J. S. Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am J Hum Genet. 1992 Jun;50(6):1211–1217. [PMC free article] [PubMed] [Google Scholar]
  30. Toda T., Ikegawa S., Okui K., Kondo E., Saito K., Fukuyama Y., Yoshioka M., Kumagai T., Suzumori K., Kanazawa I. Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy: evidence for strong linkage disequilibrium. Am J Hum Genet. 1994 Nov;55(5):946–950. [PMC free article] [PubMed] [Google Scholar]
  31. Udd B. Limb-girdle type muscular dystrophy in a large family with distal myopathy: homozygous manifestation of a dominant gene? J Med Genet. 1992 Jun;29(6):383–389. doi: 10.1136/jmg.29.6.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weber J. L., Polymeropoulos M. H., May P. E., Kwitek A. E., Xiao H., McPherson J. D., Wasmuth J. J. Mapping of human chromosome 5 microsatellite DNA polymorphisms. Genomics. 1991 Nov;11(3):695–700. doi: 10.1016/0888-7543(91)90077-r. [DOI] [PubMed] [Google Scholar]
  33. Yamanouchi Y., Arikawa E., Arahata K., Ozawa E., Nonaka I. Limb-girdle muscular dystrophy: clinical and pathologic reevaluation. J Neurol Sci. 1995 Mar;129(1):15–20. doi: 10.1016/0022-510x(94)00231-c. [DOI] [PubMed] [Google Scholar]
  34. Yamaoka L. H., Westbrook C. A., Speer M. C., Gilchrist J. M., Jabs E. W., Schweins E. G., Stajich J. M., Gaskell P. C., Roses A. D., Pericak-Vance M. A. Development of a microsatellite genetic map spanning 5q31-q33 and subsequent placement of the LGMD1A locus between D5S178 and IL9. Neuromuscul Disord. 1994 Sep-Nov;4(5-6):471–475. doi: 10.1016/0960-8966(94)90086-8. [DOI] [PubMed] [Google Scholar]

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