Gene Markers

Overview

Research in this laboratory, under the direction of Dr. William J. Kimberling, is concerned with identification of genes and the localization of these genes to the human gene map. Syndromes currently under study include:

  • Usher
  • Branchio-oto-renal
  • Autosomal dominant progressive hearing loss
  • Nonsydromic recessive hearing loss

A major focus of the research program has been on Usher syndrome. Eleven different Usher genes have been discovered; one has been identified as the myosin VIIa gene on chromosome 11q, and a second is a novel basement membrane protein called Usherin. Our laboratory is now attempting to isolate and clone other Usher genes. The series of Usher families under study is the largest ever assembled.

Future research will be centered on the causes of variation in the expression of the Usher genes, on the development of animal models (with Dr. Cosgrove) and on methods of gene therapy.

We are now collaborating with Dr. Richard Smith at the University of Iowa to map genes causing progressive hearing loss. This project started in the spring of 2008 and we have already identified several new genes.

Branchio-oto-renal syndrome has another major project of the laboratory. One gene has been located on chromosome 8. Unfortunately, funding for this project has lapsed and the study has been put in abeyance until the necessry funding is obtained.

Nonsyndromic recessive hearing loss is another major study focus. NSRHL accounts for 80 percent of all hereditary cases. It has been estimated that 15 to 300 genes may be involved. Our work is now directed towards finding these genes.

Facilities

The laboratory is equipped for most techniques in gene marker analysis including typing of DNA polymorphisms. It has the power supplies and electrophoretic equipment required for starch, acrylamide, and agarose electrophoresis isoelectric focusing. It also has a darkroom, ultracentrifuge, ultra-low temperature freezers, sterile hood incubators and autoclave.

Representative Publications

Kimberling, W.J. & Moller, C. (1995). Clinical and molecular genetics of usher syndrome. J. Am. Acad. Audiol. 6, 63-72.

Steel, K.P. & Kimberling, W.J. (1996). Approaches to understanding the molecular genetics of hearing and deafness. In T. R. Van de Water, A. N. Popper & R. Fay (Eds.), Clinical Aspects of Hearing (Springer Handbook of Auditory Research). Springer, New York, pp. 10-40.

Weston, M.D., Kelley, P.M., Overbeck, L.D., Wagenaar, M., Hasson, T., Orten, D.J., Chen, Z.-Y., Corey, D., Mooseker, M., Sumegi, J., Cremers, C.W.R.J., Moller, C., Jacobson, S.G., Gorin, M.B. & Kimberling, W.J. (1996). Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. Am. J. Hum. Genet. 59, 1074-1083.

Cohn, E.S., Kelley, P.M., Fowler, T., Gorga, M.P., Lefkowitz, D., Kuehn, H., Schaefer, G.B., Gobar, L.S., Hahn, F.J., Harris, D.J. & Kimberling, W.J. (1999). Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics 103, 546-550.

Pieke-Dahl, S.A., Moller, C.G., Kelley, P.M., Astuto, L.M., Cremers, C.W.R.J., Gorin, M.B. & Kimberling, W.J. (2000). Genetic heterogeneity of Usher syndrome type II: Localisation to chromosome 5q. J. Med. Genet. 37, 256-262.

Weston, M.D., Eudy, J.D., Fujita, S., Yao, S.-F., Usami, S.I., Cremers, C.W.R.J., Greenberg, J., Ramesar, R., Martini, A., Moller, C., Smith, R.J.H., Sumegi, J., Kimberling, W.J. & Greenburg, J. (2000). Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa. Am. J. Hum. Genet. 66, 1199-1210.

Kimberling, W.J. & Lindenmuth, A.F. (2006). The Usher syndromes. Sem. Hear. 27, 182-192.

Sadeghi, A.M., Eriksson, K., Kimberling, W.J., Sjostrom, A. & Moller, C. (2006). Longterm visual prognosis in Usher syndrome types 1 and 2. Acta Ophthalmol. Scand. 84, 537-544.

Varga, R., Avenarius, M.R., Kelley, P.M., Keats, B.J., Berlin, C.I., Hood, L.J., Morlet, T.G., Brashears, S.M., Starr, A., Cohn, E.S., Smith, R.J. & Kimberling, W.J. (2006). OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature- sensitive auditory neuropathy allele. J. Med. Genet. 43, 576-581.

Azaiez, H., Yang, T., Prasad, S., Sorensen, J.L., Nishimura, C.J., Kimberling, W.J. & Smith, R.J. (2007). Genotype-phenotype correlations for SLC26A4-related deafness. Hum. Genet. 122, 451-457.

Cremers, F.P.M., Kimberling, W.J., Külm, M., De Brouwer, A.P., van Wijk, E., te Brinke, H., Cremers, C.W.R.J., Hoefsloot, L.H., Banfi, S., Simonelli, F., Fleischhauer, J.C., Berger, W., Kelley, P.M., Haralambous, E., Bitner-Glindzicz, M., Webster, A., Saihan, Z., De Baere, E., Leroy, B.P., Silvestri, G., McKay, G.J., Koenekoop, R.K., Millan, J.M., Rosenberg, T., Joensuu, T., Sankila, E., Weil, D., Weston, M., Wissinger, B. & Kremer, H. (2007). Development of a genotyping microarray for Usher syndrome. J. Med. Genet. 44, 153-160.

Fishman, G.A., Bozbeyoglu, S., Massof, R.W. & Kimberling, W.J. (2007). Natural course of visual field loss in patients with type 2 Usher syndrome. Retina 27, 601-608.

Hoskins, B.E., Cramer, C.H.I., Silvius, D., Zou, D., Raymond, R.M.Jr., Orten, D.J., Kimberling, W.J., Smith, R.J.H., Weil, D., Petit, C., Otto, E.A., Xu, P.X. & Hildebrandt, F. (2007). Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am. J. Hum. Genet. 80, 800-804.

Kimberling, W.J. & Lindenmuth, A.F. (2007). Genetics, hereditary hearing loss, and ethics. Sem. Hear. 28, 216-225.

Kochhar, A., Fischer, S.M., Kimberling, W.J. & Smith, R.J. (2007). Branchio-oto-renal syndrome. Am. J. Med. Genet. 143, 1671-1678.

Smith, R.J., Alexander, J., Barlow, P.N., Botto, M., Cassavant, T.L., Cook, H.T., de Cordoba, S.R., Hageman, G.S., Jokiranta, T.S., Kimberling, W.J., Lambris, J.D., Lanning, L.D., Levidiotis, V., Licht, C., Lutz, H.U., Meri, S., Pickering, M.C., Quigg, R.J., Rops, A.L., Salant, D.J., Sethi, S., Thurman, J.M., Tully, H.F., Tully, S.P., van der Vlag, J., Walker, P.D., Wurzner, R., Zipfel, P.F. & Dense Deposit Disease Focus Group. (2007). New approaches to the treatment of dense deposit disease. J. Am. Soc. Nephrol. 18, 2447-2456.

Gopalarao, D., Kimberling, W.J., Jesteadt, W., Kelley, P.M., Beauchaine, K.L. & Cohn, E.S. (2008). Is hearing loss due to mutations in the Connexin 26 gene progressive? Int. J. Audiol. 47, 11-20.

Herrera, W., Aleman, T., Cideciyan, A.V., Roman, A.J., Banin, E., Ben-Yosef, T., Gardner, L.M., Sumaroka, A., Windsor, E.A., Schwartz, S.B., Stone, E.M., Liu, X.Z., Kimberling, W.J. & Jacobsen, S.G. (2008). Retinal disease in Usher syndrome III caused by mutations in the clarin-1 gene. Invest. Ophthalmol. Vis. Sci. 49, 2651-2660.

Hildebrand, M.S., Sorensen, J.L., Jensen, M., Kimberling, W.J. & Smith, R.J.H. (2008). Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS1. Am. J. Med. Genet. Part A (in press).

Jacobsen, S.G., Cideciyan, A.V., Aleman, T.S., Sumaroka, A., Roman, A.J., Gardner, L.M., Prosser, H.M., Mishra, M., Bech-Hansen, N.T., Herrera, W., Schwartz, S.B., Liu, X.Z., Kimberling, W.J., Steel, K.P. & Williams, D.S. (2008). Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Hum. Mol. Genet. (in press) [Epub ahead of print].

Kochhar, A., Orten, D.J., Sorensen, J.L., Fischer, S.M., Cremers, C.W., Kimberling, W.J. & Smith, R.J. (2008). SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Hum. Mutat. 29, 565-576.

Orten, D.J., Fischer, S.M., Sorensen, J.L., Radhakrishna, U., Cremers, C., Marres, H.A., Van Camp, G., Welch, K.O., Smith, R.J. & Kimberling, W.J. (2008). Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Hum. Mutat. 29, 537-544.

Oshima, A., Jaijo, T., Aller, E., Millan, J.M., Carney, C., Usami, S., Moller, C. & Kimberling, W.J. (2008). Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Hum. Mutat. 29, E37-E46.

Tamayo, M.L., Lopez, G., Gelvez, N., Medina, D., Kimberling, W.J., Rodriguez, V., Tamayo, G.E. & Bernal, J.E. (2008). Genetic counseling in Usher syndrome: linkage and mutational analysis of 10 Colombian families. Genet. Couns. 19, 15-27.