WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome.
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.
Kim
Hyung-Goo
HG
Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912, USA. hkim@chgr.mgh.harvard.edu
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
D000293:Adolescent; D000818:Animals; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011627:Puberty / Q000235:genetics*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D020798:Two-Hybrid System Techniques; D015027:Zebrafish; D000099260:Empty Spiracles Homeobox Proteins; D000092468:Bromodomain Containing Proteins
D018398:Homeodomain Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C435527:WDR11 protein, human; D000092468:Bromodomain Containing Proteins