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. 1999 Jan;64(1):126–135. doi: 10.1086/302206

Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping.

B Cormand 1, K Avela 1, H Pihko 1, P Santavuori 1, B Talim 1, H Topaloglu 1, A de la Chapelle 1, A E Lehesjoki 1
PMCID: PMC1377710  PMID: 9915951

Abstract

Muscle-eye-brain disease (MEB) is an autosomal recessive disease of unknown etiology characterized by severe mental retardation, ocular abnormalities, congenital muscular dystrophy, and a polymicrogyria-pachygyria-type neuronal migration disorder of the brain. A similar combination of muscle and brain involvement is also seen in Walker-Warburg syndrome (WWS) and Fukuyama congenital muscular dystrophy (FCMD). Whereas the gene underlying FCMD has been mapped and cloned, the genetic location of the WWS gene is still unknown. Here we report the assignment of the MEB gene to chromosome 1p32-p34 by linkage analysis and homozygosity mapping in eight families with 12 affected individuals. After a genomewide search for linkage in four affected sib pairs had pinpointed the assignment to 1p, the MEB locus was more precisely assigned to a 9-cM interval flanked by markers D1S200 proximally and D1S211 distally. Multipoint linkage analysis gave a maximum LOD score of 6.17 at locus D1S2677. These findings provide a starting point for the positional cloning of the disease gene, which may play an important role in muscle function and brain development. It also provides an opportunity to test other congenital muscular dystrophy phenotypes, in particular WWS, for linkage to the same locus.

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Selected References

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

  1. Avela K., Lipsanen-Nyman M., Perheentupa J., Wallgren-Pettersson C., Marchand S., Fauré S., Sistonen P., de la Chapelle A., Lehesjoki A. E. Assignment of the mulibrey nanism gene to 17q by linkage and linkage-disequilibrium analysis. Am J Hum Genet. 1997 Apr;60(4):896–902. [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Calof A. L., Lander A. D. Relationship between neuronal migration and cell-substratum adhesion: laminin and merosin promote olfactory neuronal migration but are anti-adhesive. J Cell Biol. 1991 Nov;115(3):779–794. doi: 10.1083/jcb.115.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Campbell K. P. Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage. Cell. 1995 Mar 10;80(5):675–679. doi: 10.1016/0092-8674(95)90344-5. [DOI] [PubMed] [Google Scholar]
  5. Collins A., Frezal J., Teague J., Morton N. E. A metric map of humans: 23,500 loci in 850 bands. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14771–14775. doi: 10.1073/pnas.93.25.14771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  7. Dobyns W. B., Pagon R. A., Armstrong D., Curry C. J., Greenberg F., Grix A., Holmes L. B., Laxova R., Michels V. V., Robinow M. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet. 1989 Feb;32(2):195–210. doi: 10.1002/ajmg.1320320213. [DOI] [PubMed] [Google Scholar]
  8. Dubowitz V. 50th ENMC International Workshop: congenital muscular dystrophy. 28 February 1997 to 2 March 1997, Naarden, The Netherlands. Neuromuscul Disord. 1997 Dec;7(8):539–547. [PubMed] [Google Scholar]
  9. Echenne B., Arthuis M., Billard C., Campos-Castello J., Castel Y., Dulac O., Fontan D., Gauthier A., Kulakowski S., De Meuron G. Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile. J Neurol Sci. 1986 Aug;75(1):7–22. doi: 10.1016/0022-510x(86)90046-8. [DOI] [PubMed] [Google Scholar]
  10. Engvall E., Earwicker D., Day A., Muir D., Manthorpe M., Paulsson M. Merosin promotes cell attachment and neurite outgrowth and is a component of the neurite-promoting factor of RN22 schwannoma cells. Exp Cell Res. 1992 Jan;198(1):115–123. doi: 10.1016/0014-4827(92)90156-3. [DOI] [PubMed] [Google Scholar]
  11. Federico A., Dotti M. T., Malandrini A., Guazzi G. C., Hayek G., Simonati A., Rizzuto N., Toti P. Cerebro-ocular dysplasia and muscular dystrophy: report of two cases. Neuropediatrics. 1988 May;19(2):109–112. doi: 10.1055/s-2008-1052412. [DOI] [PubMed] [Google Scholar]
  12. Fukuyama Y., Osawa M., Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type - clinical, genetic and pathological considerations. Brain Dev. 1981;3(1):1–29. doi: 10.1016/s0387-7604(81)80002-2. [DOI] [PubMed] [Google Scholar]
  13. Hagg T., Portera-Cailliau C., Jucker M., Engvall E. Laminins of the adult mammalian CNS; laminin-alpha2 (merosin M-) chain immunoreactivity is associated with neuronal processes. Brain Res. 1997 Aug 1;764(1-2):17–27. doi: 10.1016/s0006-8993(97)00419-8. [DOI] [PubMed] [Google Scholar]
  14. Haltia M., Leivo I., Somer H., Pihko H., Paetau A., Kivelä T., Tarkkanen A., Tomé F., Engvall E., Santavuori P. Muscle-eye-brain disease: a neuropathological study. Ann Neurol. 1997 Feb;41(2):173–180. doi: 10.1002/ana.410410208. [DOI] [PubMed] [Google Scholar]
  15. Hayashi Y. K., Chou F. L., Engvall E., Ogawa M., Matsuda C., Hirabayashi S., Yokochi K., Ziober B. L., Kramer R. H., Kaufman S. J. Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet. 1998 May;19(1):94–97. doi: 10.1038/ng0598-94. [DOI] [PubMed] [Google Scholar]
  16. Hayashi Y. K., Engvall E., Arikawa-Hirasawa E., Goto K., Koga R., Nonaka I., Sugita H., Arahata K. Abnormal localization of laminin subunits in muscular dystrophies. J Neurol Sci. 1993 Oct;119(1):53–64. doi: 10.1016/0022-510x(93)90191-z. [DOI] [PubMed] [Google Scholar]
  17. Helbling-Leclerc A., Zhang X., Topaloglu H., Cruaud C., Tesson F., Weissenbach J., Tomé F. M., Schwartz K., Fardeau M., Tryggvason K. Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet. 1995 Oct;11(2):216–218. doi: 10.1038/ng1095-216. [DOI] [PubMed] [Google Scholar]
  18. Hellsten E., Vesa J., Heiskanen M., Mäkelä T. P., Järvelä I., Cowell J. K., Mead S., Alitalo K., Palotie A., Peltonen L. Identification of YAC clones for human chromosome 1p32 and physical mapping of the infantile neuronal ceroid lipofuscinosis (INCL) locus. Genomics. 1995 Jan 20;25(2):404–412. doi: 10.1016/0888-7543(95)80040-s. [DOI] [PubMed] [Google Scholar]
  19. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  20. Kobayashi K., Nakahori Y., Miyake M., Matsumura K., Kondo-Iida E., Nomura Y., Segawa M., Yoshioka M., Saito K., Osawa M. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998 Jul 23;394(6691):388–392. doi: 10.1038/28653. [DOI] [PubMed] [Google Scholar]
  21. Korinthenberg R., Palm D., Schlake W., Klein J. Congenital muscular dystrophy, brain malformation and ocular problems (muscle, eye and brain disease) in two German families. Eur J Pediatr. 1984 Apr;142(1):64–68. doi: 10.1007/BF00442595. [DOI] [PubMed] [Google Scholar]
  22. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  23. Lander E. S., Botstein D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987 Jun 19;236(4808):1567–1570. doi: 10.1126/science.2884728. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Leyten Q. H., Gabreëls F. J., Renier W. O., Renkawek K., ter Laak H. J., Mullaart R. A. Congenital muscular dystrophy with eye and brain malformations in six Dutch patients. Neuropediatrics. 1992 Dec;23(6):316–320. doi: 10.1055/s-2008-1071365. [DOI] [PubMed] [Google Scholar]
  26. Mielke R., Lu J. H., Kowalewski S. Zerebro-okulo-muskuläres Syndrom. Helv Paediatr Acta. 1986 Oct;41(4):369–376. [PubMed] [Google Scholar]
  27. Moghadaszadeh B., Desguerre I., Topaloglu H., Muntoni F., Pavek S., Sewry C., Mayer M., Fardeau M., Tomé F. M., Guicheney P. Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36. Am J Hum Genet. 1998 Jun;62(6):1439–1445. doi: 10.1086/301882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Murray J. C., Buetow K. H., Weber J. L., Ludwigsen S., Scherpbier-Heddema T., Manion F., Quillen J., Sheffield V. C., Sunden S., Duyk G. M. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science. 1994 Sep 30;265(5181):2049–2054. doi: 10.1126/science.8091227. [DOI] [PubMed] [Google Scholar]
  29. Pihko H., Lappi M., Raitta C., Sainio K., Valanne L., Somer H., Santavuori P. Ocular findings in muscle-eye-brain (MEB) disease: a follow-up study. Brain Dev. 1995 Jan-Feb;17(1):57–61. doi: 10.1016/0387-7604(94)00101-3. [DOI] [PubMed] [Google Scholar]
  30. Raitta C., Lamminen M., Santavuori P., Leisti J. Ophthalmological findings in a new syndrome with muscle, eye and brain involvement. Acta Ophthalmol (Copenh) 1978 Jun;56(3):465–472. doi: 10.1111/j.1755-3768.1978.tb05700.x. [DOI] [PubMed] [Google Scholar]
  31. Ranta S., Pihko H., Santavuori P., Tahvanainen E., de la Chapelle A. Muscle-eye-brain disease and Fukuyama type congenital muscular dystrophy are not allelic. Neuromuscul Disord. 1995 May;5(3):221–225. doi: 10.1016/0960-8966(94)00058-h. [DOI] [PubMed] [Google Scholar]
  32. Santavuori P., Pihko H., Sainio K., Lappi M., Somer H., Haltia M., Raitta C., Ketonen L., Leisti J. Muscle-eye-brain disease and Walker-Warburg syndrome. Am J Med Genet. 1990 Jul;36(3):371–374. doi: 10.1002/ajmg.1320360334. [DOI] [PubMed] [Google Scholar]
  33. Santavuori P., Somer H., Sainio K., Rapola J., Kruus S., Nikitin T., Ketonen L., Leisti J. Muscle-eye-brain disease (MEB) Brain Dev. 1989;11(3):147–153. doi: 10.1016/s0387-7604(89)80088-9. [DOI] [PubMed] [Google Scholar]
  34. Santavuori P., Valanne L., Autti T., Haltia M., Pihko H., Sainio K. Muscle-eye-brain disease: clinical features, visual evoked potentials and brain imaging in 20 patients. Eur J Paediatr Neurol. 1998;2(1):41–47. doi: 10.1016/1090-3798(98)01004-1. [DOI] [PubMed] [Google Scholar]
  35. Schuler G. D., Boguski M. S., Stewart E. A., Stein L. D., Gyapay G., Rice K., White R. E., Rodriguez-Tomé P., Aggarwal A., Bajorek E. A gene map of the human genome. Science. 1996 Oct 25;274(5287):540–546. [PubMed] [Google Scholar]
  36. Speleman F., Van Camp G., Van Roy N. Reassignment of MYCL1 to human chromosome 1p34.3 by fluorescence in situ hybridization. Cytogenet Cell Genet. 1996;72(2-3):189–190. doi: 10.1159/000134185. [DOI] [PubMed] [Google Scholar]
  37. Takada K., Nakamura H., Tanaka J. Cortical dysplasia in congenital muscular dystrophy with central nervous system involvement (Fukuyama type). J Neuropathol Exp Neurol. 1984 Jul;43(4):395–407. doi: 10.1097/00005072-198407000-00005. [DOI] [PubMed] [Google Scholar]
  38. Terwilliger J. D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet. 1995 Mar;56(3):777–787. [PMC free article] [PubMed] [Google Scholar]
  39. Toda T., Segawa M., Nomura Y., Nonaka I., Masuda K., Ishihara T., Sakai M., Tomita I., Origuchi Y., Suzuki M [corrected to Sakai M. ]. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet. 1993 Nov;5(3):283–286. doi: 10.1038/ng1193-283. [DOI] [PubMed] [Google Scholar]
  40. Topaloğlu H., Cila A., Taşdemir A. H., Saatçi I. Congenital muscular dystrophy with eye and brain involvement. The Turkish experience in two cases. Brain Dev. 1995 Jul-Aug;17(4):271–275. doi: 10.1016/0387-7604(95)00047-f. [DOI] [PubMed] [Google Scholar]
  41. Valanne L., Pihko H., Katevuo K., Karttunen P., Somer H., Santavuori P. MRI of the brain in muscle-eye-brain (MEB) disease. Neuroradiology. 1994 Aug;36(6):473–476. doi: 10.1007/BF00593687. [DOI] [PubMed] [Google Scholar]
  42. Voit T. Congenital muscular dystrophies: 1997 update. Brain Dev. 1998 Mar;20(2):65–74. doi: 10.1016/s0387-7604(97)00094-6. [DOI] [PubMed] [Google Scholar]
  43. de la Chapelle A. Disease gene mapping in isolated human populations: the example of Finland. J Med Genet. 1993 Oct;30(10):857–865. doi: 10.1136/jmg.30.10.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. van der Knaap M. S., Smit L. M., Barth P. G., Catsman-Berrevoets C. E., Brouwer O. F., Begeer J. H., de Coo I. F., Valk J. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol. 1997 Jul;42(1):50–59. doi: 10.1002/ana.410420110. [DOI] [PubMed] [Google Scholar]

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