Evidence for genetic heterogeneity in male pseudohermaphroditism due to leydig cell hypoplasia

Leydig cell aplasia or hypoplasia is a rare form of male pseudohermaphrodit ism resulting from inadequate fetal testicular Leydig cell differentiation. Affected individuals presented a wide phenotypic spectrum, ranging from co mplete female external genitalia to males with micropenis. Recessive mutati ons in the LH receptor gene have been identified as responsible for the con dition. The majority of these mutations are point mutations and have been l ocated in exon 11 of the gene. In this study, we report the molecular chara cterization of the LH receptor gene in three siblings with Leydig cell hypo plasia. After sequencing the 11 exons of the gene, no deleterious mutations were detected in any patient. However, we identified a previously describe d polymorphism in exon 11. In patients 1 and 3 DNA sequencing revealed a C to T substitution at nucleotide 1065; both patients were homozygous GAT/GAT at codon 355. In contrast, patient 2 was homozygous GAC/GAC, whereas the f ather and one unaffected sister were heterozygous GAC/GAT at this polymorph ic site. These results exclude that Leydig cell hypoplasia in this family i s due to a mutation in the LH receptor gene and provide evidence that defec ts in other loci may also result in failure of Leydig cell differentiation, demonstrating, for the first time, that Leydig cell hypoplasia is a geneti cally heterogeneous condition.