Drosophila basement membrane collagen col4a1 mutations cause severe myopathy

Ildikó Kelemen-Valkony, Márton Kiss, Judit Csiha, András Kiss, Urs Bircher, János Szidonya, Péter Maróy, Gábor Juhász, Orbán Komonyi, Katalin Csiszár, Mátyás Mink

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Recent data from clinical and mammalian genetic studies indicate that COL4A1 mutations manifest with basement membrane defects that result in muscle weakness, cramps, contractures, dystrophy and atrophy. In-depth studies of mutant COL4A1-associated muscle phenotype, however, are lacking and significant details of the muscle-specific pathomechanisms remain unknown. In this study, we have used a comprehensive set of Drosophila col4a1 and col4a2 mutants and a series of genetic and mutational analyses, gene, protein expression, and immunohistochemistry experiments in order to establish a Drosophila model and address some of these questions. The Drosophila genome contains two type IV collagen genes, col4a1 and col4a2. Mutant heterozygotes of either gene are viable and fertile, whereas homozygotes are lethal. In complementation analysis of all known mutants of the locus and a complementation matrix derived from these data we have identified the dominant lesions within the col4a1, but not within the col4a2 gene. Expression of a col4a1 transgene partially rescued the dominant and recessive mutant col4a1 alleles but not the col4a2 mutations that were all recessive. Partial complementation suggested that col4a1 gene mutations have strong antimorph effect likely due to the incorporation of the mutant protein into the triple helix. In col4a1 mutants, morphological changes of the oviduct muscle included severe myopathy with centronuclear myofibers leading to gradual development of female sterility. In larval body wall muscles ultrastructural changes included disturbance of A and I bands between persisting Z bands. In the most severely affected DTS-L3 mutant, we have identified four missense mutations within the coding region of the col4a1 gene two of which affected the Y within the Gly-X-Y unit and a 3' UTR point mutation. In conclusion, our Drosophila mutant series may serve as an effective model to uncover the mechanisms by which COL4A1 mutations result in compromised myofiber-basement membrane interactions and aberrant muscle function.

Original languageEnglish
Pages (from-to)29-37
Number of pages9
JournalMatrix Biology
Volume31
Issue number1
DOIs
Publication statusPublished - Jan 1 2012

Keywords

  • Drosophila
  • Multiple mutations
  • Myopathy
  • Type IV collagen

ASJC Scopus subject areas

  • Molecular Biology

Fingerprint Dive into the research topics of 'Drosophila basement membrane collagen col4a1 mutations cause severe myopathy'. Together they form a unique fingerprint.

  • Cite this

    Kelemen-Valkony, I., Kiss, M., Csiha, J., Kiss, A., Bircher, U., Szidonya, J., Maróy, P., Juhász, G., Komonyi, O., Csiszár, K., & Mink, M. (2012). Drosophila basement membrane collagen col4a1 mutations cause severe myopathy. Matrix Biology, 31(1), 29-37. https://doi.org/10.1016/j.matbio.2011.09.004