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A Novel Human Sex-Determining Gene Linked to Xp11.21-11.23

Centre for Cellular and Molecular Biology (S.R., K.T., D.S.R., L.S.), Hyderabad 500 007, India; Institute of Reproductive Medicine (N.J.G., B.C.), Salt Lake, Kolkata 700 091, India; Division of Human Genetics (N.L., S.R.), St. John’s Medical College, Bangalore 560 034, India; Department of Genetics, Postgraduate Institute of Basic Medical Sciences (R.G.N., V.K., S.T.S., P.M.G.), University of Madras, Chennai 600 113, India; and KMC Life Science Centre (P.M.G.), Manipal Academy of Higher Education, Manipal 576 104, India

Address all correspondence and requests for reprints to: Dr. K. Thangaraj and Dr. Lalji Singh, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India. E-mail: thangs@ccmb.res.in and lalji{at}ccmb.res.in.

Context: The molecular basis for about 70–80% of 46,XY sex-reversed females remains unexplained, because they carry normal copies of the genes (SRY, SOX9, DAX1, DMRT, SF1, WT1) involved in sex determination pathway.

Objective: The objective of this study is to map the chromosomal locus responsible for an unexplained sex-reversed phenotype.

Design: The study implemented a genome-wide scan using families with multiple sex-reversed individuals.

Setting: The patients, along with the family members, were selected from different hospitals/reproductive centers.

Participants: Sex-reversed individuals and their siblings and parents participated in the study.

Main Outcome Measures: Identification of the chromosomal locus responsible for sex reversal in these families and sequence analysis of candidate genes were the main outcome measures.

Results: Parametric linkage analysis revealed a maximum two-point LOD score of 5.70 with marker DXS991 (Xp11.21) and 4.57 with marker DXS1039 (Xp11.23-Xp11.22), and a multipoint LOD score of 5.77 with marker DXS991 and 5.22 with marker DXS1039. The two markers (DXS991 and DXS1039) with highest LOD score span approximately 3.41 cM (75.79–79.2 cM) on the short arm of the X-chromosome.

Conclusion: Our findings provide evidence for a major susceptibility locus for sex reversal/gonadal dysgenesis on the short arm of the X-chromosome (Xp11.21-11.23). Furthermore, molecular exploration of the expression of candidate genes in the embryonic gonad/gonadal ridge will help in the identification of the underlying gene for sex reversal.

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