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. 1998 Aug 15;102(4):844–852. doi: 10.1172/JCI3705

Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models.

W Kuang 1, H Xu 1, P H Vachon 1, L Liu 1, F Loechel 1, U M Wewer 1, E Engvall 1
PMCID: PMC508948  PMID: 9710454

Abstract

Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.

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Selected References

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  1. Andre F., Filippi P., Feracci H. Merosin is synthesized by thyroid cells in primary culture irrespective of cellular organization. J Cell Sci. 1994 Jan;107(Pt 1):183–193. doi: 10.1242/jcs.107.1.183. [DOI] [PubMed] [Google Scholar]
  2. Arahata K., Ishii H., Hayashi Y. K. Congenital muscular dystrophies. Curr Opin Neurol. 1995 Oct;8(5):385–390. doi: 10.1097/00019052-199510000-00011. [DOI] [PubMed] [Google Scholar]
  3. Beaulieu J. F., Vachon P. H. Reciprocal expression of laminin A-chain isoforms along the crypt-villus axis in the human small intestine. Gastroenterology. 1994 Apr;106(4):829–839. doi: 10.1016/0016-5085(94)90740-4. [DOI] [PubMed] [Google Scholar]
  4. Chang A. C., Wadsworth S., Coligan J. E. Expression of merosin in the thymus and its interaction with thymocytes. J Immunol. 1993 Aug 15;151(4):1789–1801. [PubMed] [Google Scholar]
  5. Cox G. A., Cole N. M., Matsumura K., Phelps S. F., Hauschka S. D., Campbell K. P., Faulkner J. A., Chamberlain J. S. Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity. Nature. 1993 Aug 19;364(6439):725–729. doi: 10.1038/364725a0. [DOI] [PubMed] [Google Scholar]
  6. Davies K. E. Challenges in Duchenne muscular dystrophy. Neuromuscul Disord. 1997 Dec;7(8):482–486. doi: 10.1016/s0960-8966(97)00107-7. [DOI] [PubMed] [Google Scholar]
  7. Ehrig K., Leivo I., Argraves W. S., Ruoslahti E., Engvall E. Merosin, a tissue-specific basement membrane protein, is a laminin-like protein. Proc Natl Acad Sci U S A. 1990 May;87(9):3264–3268. doi: 10.1073/pnas.87.9.3264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Engvall E., Wewer U. M. Domains of laminin. J Cell Biochem. 1996 Jun 15;61(4):493–501. doi: 10.1002/(SICI)1097-4644(19960616)61:4%3C493::AID-JCB2%3E3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  9. Florini J. R., Samuel D. S., Ewton D. Z., Kirk C., Sklar R. M. Stimulation of myogenic differentiation by a neuregulin, glial growth factor 2. Are neuregulins the long-sought muscle trophic factors secreted by nerves? J Biol Chem. 1996 May 31;271(22):12699–12702. doi: 10.1074/jbc.271.22.12699. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Hauser M. A., Chamberlain J. S. Progress towards gene therapy for Duchenne muscular dystrophy. J Endocrinol. 1996 Jun;149(3):373–378. doi: 10.1677/joe.0.1490373. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Helgren M. E., Squinto S. P., Davis H. L., Parry D. J., Boulton T. G., Heck C. S., Zhu Y., Yancopoulos G. D., Lindsay R. M., DiStefano P. S. Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle. Cell. 1994 Feb 11;76(3):493–504. doi: 10.1016/0092-8674(94)90113-9. [DOI] [PubMed] [Google Scholar]
  16. Herrmann R., Straub V., Meyer K., Kahn T., Wagner M., Voit T. Congenital muscular dystrophy with laminin alpha 2 chain deficiency: identification of a new intermediate phenotype and correlation of clinical findings to muscle immunohistochemistry. Eur J Pediatr. 1996 Nov;155(11):968–976. doi: 10.1007/BF02282889. [DOI] [PubMed] [Google Scholar]
  17. Inui K., Okada S., Dickson G. Gene therapy in Duchenne muscular dystrophy. Brain Dev. 1996 Sep-Oct;18(5):357–361. doi: 10.1016/0387-7604(96)00043-5. [DOI] [PubMed] [Google Scholar]
  18. Landegren U., Kaiser R., Sanders J., Hood L. A ligase-mediated gene detection technique. Science. 1988 Aug 26;241(4869):1077–1080. doi: 10.1126/science.3413476. [DOI] [PubMed] [Google Scholar]
  19. Lee C. C., Pons F., Jones P. G., Bies R. D., Schlang A. M., Leger J. J., Caskey C. T. Mdx transgenic mouse: restoration of recombinant dystrophin to the dystrophic muscle. Hum Gene Ther. 1993 Jun;4(3):273–281. doi: 10.1089/hum.1993.4.3-273. [DOI] [PubMed] [Google Scholar]
  20. Leivo I., Engvall E. Merosin, a protein specific for basement membranes of Schwann cells, striated muscle, and trophoblast, is expressed late in nerve and muscle development. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1544–1548. doi: 10.1073/pnas.85.5.1544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Madrid R. E., Jaros E., Cullen M. J., Bradley W. G. Genetically determined defect of Schwann cell basement membrane in dystrophic mouse. Nature. 1975 Sep 25;257(5524):319–321. doi: 10.1038/257319a0. [DOI] [PubMed] [Google Scholar]
  22. Matsumura K., Yamada H., Saito F., Sunada Y., Shimizu T. Peripheral nerve involvement in merosin-deficient congenital muscular dystrophy and dy mouse. Neuromuscul Disord. 1997 Jan;7(1):7–12. doi: 10.1016/s0960-8966(96)00402-6. [DOI] [PubMed] [Google Scholar]
  23. Meier H., Southard J. L. Muscular dystrophy in the mouse caused by an allele at the dy-locus. Life Sci. 1970 Feb 8;9(3):137–144. doi: 10.1016/0024-3205(70)90306-1. [DOI] [PubMed] [Google Scholar]
  24. Michelson A. M., Russell E. S., Harman P. J. Dystrophia Muscularis: A HEREDITARY PRIMARY MYOPATHY IN THE HOUSE MOUSE. Proc Natl Acad Sci U S A. 1955 Dec 15;41(12):1079–1084. doi: 10.1073/pnas.41.12.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miyagoe Y., Hanaoka K., Nonaka I., Hayasaka M., Nabeshima Y., Arahata K., Nabeshima Y., Takeda S. Laminin alpha2 chain-null mutant mice by targeted disruption of the Lama2 gene: a new model of merosin (laminin 2)-deficient congenital muscular dystrophy. FEBS Lett. 1997 Sep 22;415(1):33–39. doi: 10.1016/s0014-5793(97)01007-7. [DOI] [PubMed] [Google Scholar]
  26. Muscat G. E., Downes M., Dowhan D. H. Regulation of vertebrate muscle differentiation by thyroid hormone: the role of the myoD gene family. Bioessays. 1995 Mar;17(3):211–218. doi: 10.1002/bies.950170307. [DOI] [PubMed] [Google Scholar]
  27. Nonaka I. Animal models of muscular dystrophies. Lab Anim Sci. 1998 Feb;48(1):8–17. [PubMed] [Google Scholar]
  28. Perkins C. S., Bray G. M., Aguayo A. J. Ongoing block of Schwann cell differentiation and deployment in dystrophic mouse spinal roots. Brain Res. 1981 Apr;227(2):213–220. doi: 10.1016/0165-3806(81)90109-7. [DOI] [PubMed] [Google Scholar]
  29. Philpot J., Sewry C., Pennock J., Dubowitz V. Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord. 1995 Jul;5(4):301–305. doi: 10.1016/0960-8966(94)00069-l. [DOI] [PubMed] [Google Scholar]
  30. Richardson L. L., Kleinman H. K., Dym M. Basement membrane gene expression by Sertoli and peritubular myoid cells in vitro in the rat. Biol Reprod. 1995 Feb;52(2):320–330. doi: 10.1095/biolreprod52.2.320. [DOI] [PubMed] [Google Scholar]
  31. Ryan M. C., Christiano A. M., Engvall E., Wewer U. M., Miner J. H., Sanes J. R., Burgeson R. E. The functions of laminins: lessons from in vivo studies. Matrix Biol. 1996 Dec;15(6):369–381. doi: 10.1016/s0945-053x(96)90157-2. [DOI] [PubMed] [Google Scholar]
  32. Shorer Z., Philpot J., Muntoni F., Sewry C., Dubowitz V. Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy. J Child Neurol. 1995 Nov;10(6):472–475. doi: 10.1177/088307389501000610. [DOI] [PubMed] [Google Scholar]
  33. Stirling C. A. Abnormalities in Schwann cell sheaths in spinal nerve roots of dystrophic mice. J Anat. 1975 Feb;119(Pt 1):169–180. [PMC free article] [PubMed] [Google Scholar]
  34. Sunada Y., Bernier S. M., Utani A., Yamada Y., Campbell K. P. Identification of a novel mutant transcript of laminin alpha 2 chain gene responsible for muscular dystrophy and dysmyelination in dy2J mice. Hum Mol Genet. 1995 Jun;4(6):1055–1061. doi: 10.1093/hmg/4.6.1055. [DOI] [PubMed] [Google Scholar]
  35. Swiatek P. J., Gridley T. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev. 1993 Nov;7(11):2071–2084. doi: 10.1101/gad.7.11.2071. [DOI] [PubMed] [Google Scholar]
  36. Tian M., Hagg T., Denisova N., Knusel B., Engvall E., Jucker M. Laminin-alpha2 chain-like antigens in CNS dendritic spines. Brain Res. 1997 Aug 1;764(1-2):28–38. doi: 10.1016/s0006-8993(97)00420-4. [DOI] [PubMed] [Google Scholar]
  37. Tomé F. M., Evangelista T., Leclerc A., Sunada Y., Manole E., Estournet B., Barois A., Campbell K. P., Fardeau M. Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III. 1994 Apr;317(4):351–357. [PubMed] [Google Scholar]
  38. Vachon P. H., Loechel F., Xu H., Wewer U. M., Engvall E. Merosin and laminin in myogenesis; specific requirement for merosin in myotube stability and survival. J Cell Biol. 1996 Sep;134(6):1483–1497. doi: 10.1083/jcb.134.6.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vuolteenaho R., Nissinen M., Sainio K., Byers M., Eddy R., Hirvonen H., Shows T. B., Sariola H., Engvall E., Tryggvason K. Human laminin M chain (merosin): complete primary structure, chromosomal assignment, and expression of the M and A chain in human fetal tissues. J Cell Biol. 1994 Feb;124(3):381–394. doi: 10.1083/jcb.124.3.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weinberg H. J., Spencer P. S., Raine C. S. Aberrant PNS development in dystrophic mice. Brain Res. 1975 May 9;88(3):532–537. doi: 10.1016/0006-8993(75)90666-6. [DOI] [PubMed] [Google Scholar]
  41. Xu H., Christmas P., Wu X. R., Wewer U. M., Engvall E. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5572–5576. doi: 10.1073/pnas.91.12.5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Xu H., Wu X. R., Wewer U. M., Engvall E. Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene. Nat Genet. 1994 Nov;8(3):297–302. doi: 10.1038/ng1194-297. [DOI] [PubMed] [Google Scholar]
  43. Yagi T., Ikawa Y., Yoshida K., Shigetani Y., Takeda N., Mabuchi I., Yamamoto T., Aizawa S. Homologous recombination at c-fyn locus of mouse embryonic stem cells with use of diphtheria toxin A-fragment gene in negative selection. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9918–9922. doi: 10.1073/pnas.87.24.9918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yurchenco P. D., Quan Y., Colognato H., Mathus T., Harrison D., Yamada Y., O'Rear J. J. The alpha chain of laminin-1 is independently secreted and drives secretion of its beta- and gamma-chain partners. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10189–10194. doi: 10.1073/pnas.94.19.10189. [DOI] [PMC free article] [PubMed] [Google Scholar]

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