Deletion of the distal short arm of chromosome 9 (9p) has been reported in a number of cases to be associated with gonadal dysgenesis and XY sex reversal, suggesting that this region contains one or more genes required in two copies for normal testis development. Recent studies have greatly narrowed the interval containing this putative autosomal testis-determining gene(s) to the distal portion of 9p24.3. We previously identified DMRT1, a human gene with sequence similarity to genes that regulate the sexual development of nematodes and insects. These genes contain a novel DNA-binding domain, which we named the DM domain. DMRT1 maps to 9p24.3 and in adults is expressed specifically in the testis. We have investigated the possible role of DM domain genes in 9p sex reversal. We identified a second DM domain gene, DMRT2, which also maps to 9p24.3. We found that point mutations in the coding region of DMRT1 and the DM domain of DMRT2 are not frequent in XY females. We showed by fluorescence in situ hybridization analysis that both genes are deleted in the smallest reported sex-reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted individuals might be due to combined hemizygosity of DMRT1 and DMRT2.
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We thank colleagues at the University of Minnesota for many helpful discussions. We thank Laura Ranum for CEPH family DNA samples, and Leann Oseth and Kelly Seifert for expert assistance with FISH, and Electra Coucouvanis for critical reading of the manuscript. We thank the following investigators for providing patient samples: D. Abuelo, O. Alfi, L. Alonso, A. Aylsworth, S. Baldinger, H. Bode, C. Booth, D. Chitayat, K. Copeland, A. de la Chapelle, D. de Ziegler, J. DiMartino-Nardi, C. Disteche, P. Donahoe, J. Fink, S. Finkernagel, J. German, Dr Hahn, M.J. Hajianpour, J. Hersh, P. Hertweck, P. Jayakar, N. Johnson, K. Keppler, K. Kreder, D. Langdon, J.L. Ross, C.C. Lin, B. Lippe, M. Lipson, P.W. Marsh, L. Martin, P. McDonough, B. McGillivray, R. McVie, J. Murray, M. Nance, P. O’Lague, L. Oman-Ganes, A. Pandya, B. Phillips, V. Proud, C. Quigley, I. Rosenthal, S. Russell, P. Saenger, A. Selman-Geara, M.H.K. Shokeir, I. Solomon, U. Surti, A. Taylor, K. Tezean, D. Weaver, D. Witt, J.Z. Hain, C. Yu and D. Zimmer-man. This work was supported by the Minnesota Medical Foundation (D.Z.), the University of Minnesota Graduate School (D.Z. and V.B.), the STAGE Program of the University of Minnesota (J.K.), an NIH pre-doctoral training grant (C.R.) and grants from the NIH to D.C.P., W.L.F. and D.Z.