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Absence of Mutations Involving the Lim Homeobox Domain Gene LHX9 in 46,XY Gonadal Agenesis and Dysgenesis

Immunogénétique Humaine, INSERM E0025, Institut Pasteur (C.O., M.F., K.M.), 75724 Paris, France; Dipartimento di Morfologia ed Embriologia, Università di Ferrara (C.O., M.B.), 44100 Ferrara, Italy; Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo (C.M.-F.), and Hospital das Clinicas-FMUSP, University of Sao Paulo School of Medicine (B.B.M.), 05508 Sao Paulo, Brazil; and Division of Pediatric Endocrinology, University of Miami School of Medicine (G.D.B.), Miami, Florida 33136

Address all correspondence and requests for reprints to: Dr. Ken McElreavey, INSERM, U-276, Immunogenetique Humaine, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex, France.

Abstract

The etiology of most cases of 46,XY gonadal dysgenesis in the absence of extragenital anomalies is not accounted for by mutations in the genes known to date to be involved in sex determination. We have investigated the possibility that mutations in the gene LHX9, whose murine ortholog causes isolated gonadal agenesis when inactivated, might be responsible for gonadal dysgenesis and agenesis in humans. We isolated a human LHX9 complementary DNA (cDNA), mapped the gene to the long arm of human chromosome 1, and determined its genomic structure. We found that LHX9 is highly conserved between species, sharing in particular over 98% amino acid identity. A mutational screen was performed in a sample of patients with a range of gonadal maldevelopment, including bilateral gonadal agenesis in two sisters with an opposite sex karyotype. We did not detect mutations in the open reading frame of LHX9 in the patients studied. However, the extent of between-species structural conservation suggests that LHX9 deserves further consideration as a determinant of gonadal function in humans.

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