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Discovering new genes responsible for DSDs
Summary
Our project aims to identify new genetics factors involved in rare disorders of human gonadal development using Array Comparative Genomic Hybridization (CGH).
Description
Since the discovery of SRY as a major player in human sex determination, few other genes have been identified as involved in human gonadal development, when sex is determined in the developing embryo (7 weeks gestation).
Most of these genes have been identified using mouse models or by classical genetics studies of individuals with disorders of sex development (DSD). Such people are atypical in terms of anatomic, chromosomal, or gonadal sex e.g. XX males and XY females.
Importantly, changes in known genes can only explain genetically about 20% of disorders of sex development.
The understanding of disorders of sex development (DSD) is greatly hampered by the complexity of the phenotypes, the rarity of the patients and the lack of an appropriate technique to analyse and compare such patients.
The development of high resolution CGH microarray is the next powerful tool needed to overcome these difficulties and will likely produce new information on human gonadal development. Array Comparative Genomic Hybridization (CGH) measures DNA copy number differences between a reference genome and a sample genome. Using whole-genome array CGH, we can measure copy number differences in DNA across entire genomes.
Given the complexity of phenotypes to be analysed by CGH, it is crucial to narrow down the patient numbers to be analysed to very carefully diagnosed patients.
We are currently screening several XY female patients, which harbour a normal SRY gene, for copy number differences across their entire genome.
Funding
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National Health and Medical Research Council
Selected Publications
Knower, K.C., Kelly, S., Ludbrook, L.M., Bagheri-Fam, S., Sim, H., Bernard, P., Sekido, R., Lovell-Badge, R. and Harley, V.R. (2011) Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations. PLoS One 6: e17751.
Sutton, E., Hughes, J., White, S., Sekido, R., Tan, J., Arboleda, V., Rogers, N., Knower, K., Rowley, L., Eyre, H., Rizzoti, K., McAninch, D., Goncalves, J., Slee, J., Turbitt, E., Bruno, D., Bengtsson, H., Harley, V., Vilain, E., Sinclair, A., Lovell-Badge, R. and Thomas, P. (2011) Identification of SOX3 as an XX male sex reversal gene in mice and humans. Journal of Clinical Investigation 121: 328-341
White, S., Ohnesorg, T., Notini, A., Roeszler, K., Hewitt, J., Daggag, H., Smith, C., Turbitt, E., Gustin, S., van den Bergen, J., Miles, D., Western, P., Arboleda, V., Schumacher, V., Gordon, L., Bell, K., Bengtsson, H., Speed, T., Hutson, J., Warne, G., Harley, V., Koopman, P.A., Vilain, E. and Sinclair, A. (2011) Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One 6(3): e17793
Benko, S., Gordon, C.T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., Callier, P., Malan, V., Huet, F., Molven, A., Dijoud, F., Munnich, A., Faivre, L., Amiel, J., Harley, V., Houge, G., Morel, Y. and Lyonnet, S. (2011) Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. Journal of Medical Genetics 48: 825-830
White, S., Hewitt, J., Turbitt, E., van der Zwan, Y., Hersmus, R., Drop, S., Koopman, P., Harley, V., Cools, M., Looijenga, L. and Sinclair, A. A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development. European Journal of Human Genetics 2011 Nov 9. doi: 10.1038/ejhg.2011.204. [Epub ahead of print] PMID: 22071891
Ludbrook, L. and Harley, V. (2011) Genetic mechanisms underlying 46,XY DSD with gonadal dysgenesis, Advances in Experimental Medicine and Biology 707: 87-88
Georg, I., Bagheri-Fam, S., Knower, K.C., Wieacker, P., Scherer, G. and Harley, V.R. (2010) Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis. Sexual Development 4: 321-325.