WDR11, a WD Protein that Interacts with Transcription Factor EMX1, Is Mutated in Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome

• Published in: American journal of human genetics Vol. 87; no. 4; pp. 465 - 479
• Main Authors: Kim, Hyung-Goo, Ahn, Jang-Won, Kurth, Ingo, Ullmann, Reinhard, Kim, Hyun-Taek, Kulharya, Anita, Ha, Kyung-Soo, Itokawa, Yasuhide, Meliciani, Irene, Wenzel, Wolfgang, Lee, Deresa, Rosenberger, Georg, Ozata, Metin, Bick, David P., Sherins, Richard J., Nagase, Takahiro, Tekin, Mustafa, Kim, Soo-Hyun, Kim, Cheol-Hee, Ropers, Hans-Hilger, Gusella, James F., Kalscheuer, Vera, Choi, Cheol Yong, Layman, Lawrence C.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 08.10.2010; Cell Press; Elsevier
• Subjects: Adolescent; Animals; Biological and medical sciences; Breakpoints; Chromosomes; Chromosomes, Human, Pair 10 - genetics; Endocrinopathies; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Homeodomain Proteins - genetics; Humans; Hypogonadism - genetics; Hypothalamus. Hypophysis. Epiphysis (diseases); Immunoblotting; Immunohistochemistry; Immunoprecipitation; In Situ Hybridization; In Situ Hybridization, Fluorescence; Kallmann Syndrome - genetics; Male; Medical genetics; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Microarray Analysis; Molecular and cellular biology; Mutation; Mutation, Missense - genetics; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Polymorphism, Single Nucleotide - genetics; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Puberty; Puberty - genetics; Rats; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors - genetics; Translocation, Genetic - genetics; Two-Hybrid System Techniques; Zebrafish; Endocrinopathy; Human; Hypogonadotropic hypogonadism; Nervous system diseases; Hypothalamic diseases; Idiopathic; Kallmann syndrome; Protein; Genetic disease; Genital diseases; Cerebral disorder; Malformation; Central nervous system disease; ENT disease; Genetics; Transcription factor
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2010.08.018

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 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.