Abstract

Waardenburg syndrome type I (WS1, 193500) is a significant cause of congenital deafness in humans. By means of a multipoint linkage analysis (Asher et al. 1991a), one WS1 mutation has been mapped to the chromosomal region 2q37, thus confirming and extending the findings of Foy et al. (1990). Furthermore, these linkage findings appear to confirm a prediction (Asher and Friedman 1990) that the mouse mutation Sp (Splotch) is a good model for some WS1 mutations. The long-range goals of this project are to: (1) clone the WS1 and Sp genes, (2) discover the primary defects caused by WS1 and Sp mutations, and (3) determine the mechanism(s) by which specific WS1 mutations cause deafness. The immediate goal of this research project is to clone the WS1 and Sp genes. This endeavor will be successful because of the following advantages. First, in collaboration with Dr. D. H. Johnson, a human microclone library of the human 2q37 _region was constructed. Second, Dr. Susan Naylor has provided genomic DNA from human/hamster somatic cell hybrid lines which have complementary deletions of portions of the tip of 2q covering the suspected location of WS1. Third, genomic DNA from Sp(r)/+ and +/+ mice will be used to select human microclones that map within the Sp(r) deletion. Fourth, genomic DNA samples from 2,000 interspecific backcross mice are being produced that will allow the construction of a fine-structure genetic map of clones tightly linked to the Sp-locus. Finally, in collaboration with Dr. Edward Wilcox, NIDCD, clones will be tested to determine if they are close enough to the WS1 locus to reveal differences in the physical map caused by a sporadic inversion described by Ishikiriyama et al. (1989). This selection protocol should identify a cDNA clone which detects an altered physical map in sporadic cases of Waardenburg syndrome. These studies should test directly the hypothesis that Sp and WS1 are homologous genes. If this hypothesis is true, the mouse Sp-locus will be a powerful research model to determine the primary defects caused by WS1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001160-03
Application #
2126319
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-01-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Michigan State University
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824

  Publications

Carey, M L; Friedman, T B; Asher Jr, J H et al. (1998) Septo-optic dysplasia and WS1 in the proband of a WS1 family segregating for a novel mutation in PAX3 exon 7. J Med Genet 35:248-50
DeStefano, A L; Cupples, L A; Arnos, K S et al. (1998) Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum Genet 102:499-506
Morell, R; Friedman, T B; Asher Jr, J H et al. (1997) The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1). J Med Genet 34:447-52
Morell, R; Carey, M L; Lalwani, A K et al. (1997) Three mutations in the paired homeodomain of PAX3 that cause Waardenburg syndrome type 1. Hum Hered 47:38-41
Asher Jr, J H; Harrison, R W; Morell, R et al. (1996) Effects of Pax3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation. Genomics 34:285-98
Asher Jr, J H; Sommer, A; Morell, R et al. (1996) Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome. Hum Mutat 7:30-5
Friedman, T B; Liang, Y; Weber, J L et al. (1995) A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat Genet 9:86-91
Winata, S; Arhya, I N; Moeljopawiro, S et al. (1995) Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village. J Med Genet 32:336-43
Farrer, L A; Arnos, K S; Asher Jr, J H et al. (1994) Locus heterogeneity for Waardenburg syndrome is predictive of clinical subtypes. Am J Hum Genet 55:728-37
Carey, M L; Liang, Y; Barber, T D et al. (1994) Dinucleotide repeat polymorphism at D14S542. Hum Mol Genet 3:1712

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