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. 2003 Jul;164(3):1035–1041. doi: 10.1093/genetics/164.3.1035

Mutation in intron 6 of the hamster Mitf gene leads to skipping of the subsequent exon and creates a novel animal model for the human Waardenburg syndrome type II.

Jochen Graw 1, Walter Pretsch 1, Jana Löster 1
PMCID: PMC1462622  PMID: 12871913

Abstract

In the course of analysis of ENU-induced mutations in Syrian hamsters, a novel dominant anophthalmic white mutant (Wh(V203)) with hearing loss was recovered. Because of this phenotype and a close linkage to the Tpi gene, the Mitf gene was considered as a candidate gene. In the Mitf cDNA, a deletion of 76 bp covering the entire exon 7 was detected. Further molecular analysis revealed a T --> A exchange 16 bp upstream of the end of intron 6, leading to skipping of exon 7. These 16 bp at the end of intron 6 are identical in hamster, rat, mouse, and humans, indicating high conservation during evolution and a functional importance in splicing. Since the loss of exon 7 changes the open reading frame of the MITF transcript, translation will be stopped after 10 new amino acids. The truncated protein is predicted to contain only a part of the basic region and will miss the two helical domains and the leucine zipper. The Wh(V203) mutation in the Syrian hamster affects the same functional domains of the Mitf transcription factor as the human R124X mutation, causing human Waardenburg syndrome type II. Therefore, the Wh(V203) hamster mutant provides a novel model for this particular syndrome.

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Selected References

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  1. Amae S., Fuse N., Yasumoto K., Sato S., Yajima I., Yamamoto H., Udono T., Durlu Y. K., Tamai M., Takahashi K. Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium. Biochem Biophys Res Commun. 1998 Jun 29;247(3):710–715. doi: 10.1006/bbrc.1998.8838. [DOI] [PubMed] [Google Scholar]
  2. Asher J. H., Jr, James S. C. The primary ultrastructural defect caused by anophthalmic white (Wh) in the Syrian hamster. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4371–4375. doi: 10.1073/pnas.79.14.4371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bondurand N., Pingault V., Goerich D. E., Lemort N., Sock E., Le Caignec C., Wegner M., Goossens M. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum Mol Genet. 2000 Aug 12;9(13):1907–1917. doi: 10.1093/hmg/9.13.1907. [DOI] [PubMed] [Google Scholar]
  4. Dorsky R. I., Raible D. W., Moon R. T. Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway. Genes Dev. 2000 Jan 15;14(2):158–162. [PMC free article] [PubMed] [Google Scholar]
  5. Hallsson J. H., Favor J., Hodgkinson C., Glaser T., Lamoreux M. L., Magnúsdóttir R., Gunnarsson G. J., Sweet H. O., Copeland N. G., Jenkins N. A. Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus. Genetics. 2000 May;155(1):291–300. doi: 10.1093/genetics/155.1.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hodgkinson C. A., Moore K. J., Nakayama A., Steingrímsson E., Copeland N. G., Jenkins N. A., Arnheiter H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell. 1993 Jul 30;74(2):395–404. doi: 10.1016/0092-8674(93)90429-t. [DOI] [PubMed] [Google Scholar]
  7. Jacquemin P., Lannoy V. J., O'Sullivan J., Read A., Lemaigre F. P., Rousseau G. G. The transcription factor onecut-2 controls the microphthalmia-associated transcription factor gene. Biochem Biophys Res Commun. 2001 Aug 3;285(5):1200–1205. doi: 10.1006/bbrc.2001.5294. [DOI] [PubMed] [Google Scholar]
  8. Kratochvilova J. Dominant cataract mutations detected in offspring of gamma-irradiated male mice. J Hered. 1981 Sep-Oct;72(5):302–307. doi: 10.1093/oxfordjournals.jhered.a109511. [DOI] [PubMed] [Google Scholar]
  9. Lalwani A. K., Attaie A., Randolph F. T., Deshmukh D., Wang C., Mhatre A., Wilcox E. Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family. Am J Med Genet. 1998 Dec 4;80(4):406–409. [PubMed] [Google Scholar]
  10. Lister J. A., Close J., Raible D. W. Duplicate mitf genes in zebrafish: complementary expression and conservation of melanogenic potential. Dev Biol. 2001 Sep 15;237(2):333–344. doi: 10.1006/dbio.2001.0379. [DOI] [PubMed] [Google Scholar]
  11. Lister J. A., Robertson C. P., Lepage T., Johnson S. L., Raible D. W. nacre encodes a zebrafish microphthalmia-related protein that regulates neural-crest-derived pigment cell fate. Development. 1999 Sep;126(17):3757–3767. doi: 10.1242/dev.126.17.3757. [DOI] [PubMed] [Google Scholar]
  12. Moore K. J. Insight into the microphthalmia gene. Trends Genet. 1995 Nov;11(11):442–448. doi: 10.1016/s0168-9525(00)89143-x. [DOI] [PubMed] [Google Scholar]
  13. Morell R., Spritz R. A., Ho L., Pierpont J., Guo W., Friedman T. B., Asher J. H., Jr Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). Hum Mol Genet. 1997 May;6(5):659–664. doi: 10.1093/hmg/6.5.659. [DOI] [PubMed] [Google Scholar]
  14. Nobukuni Y., Watanabe A., Takeda K., Skarka H., Tachibana M. Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A. Am J Hum Genet. 1996 Jul;59(1):76–83. [PMC free article] [PubMed] [Google Scholar]
  15. Opdecamp K., Vanvooren P., Rivière M., Arnheiter H., Motta R., Szpirer J., Szpirer C. The rat microphthalmia-associated transcription factor gene (Mitf) maps at 4q34-q41 and is mutated in the mib rats. Mamm Genome. 1998 Aug;9(8):617–621. doi: 10.1007/s003359900832. [DOI] [PubMed] [Google Scholar]
  16. Pretsch W., Neuhäuser-Klaus A., Favor J. A comparison of enzyme activity mutation frequencies in germ cells of mice (Mus musculus) and golden hamsters (Mesocricetus auratus) after exposure to 2 + 2 Gy gamma-irradiation. Mutagenesis. 2000 Jan;15(1):39–43. doi: 10.1093/mutage/15.1.39. [DOI] [PubMed] [Google Scholar]
  17. Staley J. P., Guthrie C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell. 1998 Feb 6;92(3):315–326. doi: 10.1016/s0092-8674(00)80925-3. [DOI] [PubMed] [Google Scholar]
  18. Steingrímsson E., Moore K. J., Lamoreux M. L., Ferré-D'Amaré A. R., Burley S. K., Zimring D. C., Skow L. C., Hodgkinson C. A., Arnheiter H., Copeland N. G. Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences. Nat Genet. 1994 Nov;8(3):256–263. doi: 10.1038/ng1194-256. [DOI] [PubMed] [Google Scholar]
  19. Tachibana M. A cascade of genes related to Waardenburg syndrome. J Investig Dermatol Symp Proc. 1999 Sep;4(2):126–129. doi: 10.1038/sj.jidsp.5640195. [DOI] [PubMed] [Google Scholar]
  20. Tassabehji M., Newton V. E., Liu X. Z., Brady A., Donnai D., Krajewska-Walasek M., Murday V., Norman A., Obersztyn E., Reardon W. The mutational spectrum in Waardenburg syndrome. Hum Mol Genet. 1995 Nov;4(11):2131–2137. doi: 10.1093/hmg/4.11.2131. [DOI] [PubMed] [Google Scholar]
  21. Thaung Caroline, West Katrine, Clark Brian J., McKie Lisa, Morgan Joanne E., Arnold Karen, Nolan Patrick M., Peters Jo, Hunter A. Jackie, Brown Steve D. M. Novel ENU-induced eye mutations in the mouse: models for human eye disease. Hum Mol Genet. 2002 Apr 1;11(7):755–767. doi: 10.1093/hmg/11.7.755. [DOI] [PubMed] [Google Scholar]
  22. Vachtenheim J., Novotná H. Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas. Cell Mol Biol (Noisy-le-grand) 1999 Nov;45(7):1075–1082. [PubMed] [Google Scholar]
  23. Watanabe A., Takeda K., Ploplis B., Tachibana M. Epistatic relationship between Waardenburg syndrome genes MITF and PAX3. Nat Genet. 1998 Mar;18(3):283–286. doi: 10.1038/ng0398-283. [DOI] [PubMed] [Google Scholar]
  24. Yajima I., Sato S., Kimura T., Yasumoto K., Shibahara S., Goding C. R., Yamamoto H. An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness. Hum Mol Genet. 1999 Aug;8(8):1431–1441. doi: 10.1093/hmg/8.8.1431. [DOI] [PubMed] [Google Scholar]

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