Nature Genetics
9, 160 - 164 (1995)
doi:10.1038/ng0295-160
Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor geneHannie Kremer1, Robert Kraaij2, Sergio P.A. Toledo3, Miriam Post2, Julia B. Fridman3, Cesar Y. Hayashida3, Margo van Reen1, Edwin Milgrom4, Hans-Hilger Ropers1, Edwin Mariman1, Axel P.N. Themmen2
& Han G. Brunner1
1Department of Human Genetics, University Hospital, Nijmegen, The Netherlands
2Department of Endocrinology & Reproduction, Erasmus University Rotterdam, Rotterdam, The Netherlands
3Endocrine Genetics Unit, Endocrine Division, Department of Medicine, Sao Paulo University School of Medicine, Sao Paulo, Brazil
4Unité de Récherche Hormones et Réproduction, INSERM U135, Faculté de Médecine de Bicêtre, Université de Paris, Paris, France Correspondence should be addressed to A.P.N.T. Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied two Leydig cell hypoplasia patients (siblings born to consanguineous parents), and found them to be homozygous for a missense mutation (Ala593Pro) in the sixth transmembrane domain of the luteinizing hormone (LH) receptor gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin with a normal KD, but the ligand binding does not result in increased production of cAMP. We conclude that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. These results have implications for the understanding of the development of the male genitalia.
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