Dataset Information

WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

ABSTRACT: By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for ? propeller formation and protein-protein interaction. In addition, we discovered that WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and that missense alterations reduce or abolish this interaction. Our findings suggest that impaired pubertal development in these patients results from a deficiency of productive WDR11 protein interaction.

SUBMITTER: Kim HG

PROVIDER: S-EPMC2948809 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

Kim Hyung-Goo HG Ahn Jang-Won JW Kurth Ingo I Ullmann Reinhard R Kim Hyun-Taek HT Kulharya Anita A Ha Kyung-Soo KS Itokawa Yasuhide Y Meliciani Irene I Wenzel Wolfgang W Lee Deresa D Rosenberger Georg G Ozata Metin M Bick David P DP Sherins Richard J RJ Nagase Takahiro T Tekin Mustafa M Kim Soo-Hyun SH Kim Cheol-Hee CH Ropers Hans-Hilger HH Gusella James F JF Kalscheuer Vera V Choi Cheol Yong CY Layman Lawrence C LC

American journal of human genetics 20101001 4

By defining the chromosomal breakpoint of a balanced t(10;12) translocation from a subject with Kallmann syndrome and scanning genes in its vicinity in unrelated hypogonadal subjects, we have identified WDR11 as a gene involved in human puberty. We found six patients with a total of five different heterozygous WDR11 missense mutations, including three alterations (A435T, R448Q, and H690Q) in WD domains important for β propeller formation and protein-protein interaction. In addition, we discovere ...[more]

PMID: 20887964

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Project description:Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.

Dataset Information

WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

Publications

WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.

Similar Datasets

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