LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.
Li
Yun
Y
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Pawlik
Barbara
B
Elcioglu
Nursel
N
Aglan
Mona
M
Kayserili
Hülya
H
Yigit
Gökhan
G
Percin
Ferda
F
Goodman
Frances
F
Nürnberg
Gudrun
G
Cenani
Asim
A
Urquhart
Jill
J
Chung
Boi-Dinh
BD
Ismail
Samira
S
Amr
Khalda
K
Aslanger
Ayca D
AD
Becker
Christian
C
Netzer
Christian
C
Scambler
Pete
P
Eyaid
Wafaa
W
Hamamy
Hanan
H
Clayton-Smith
Jill
J
Hennekam
Raoul
R
Nürnberg
Peter
P
Herz
Joachim
J
Temtamy
Samia A
SA
Wollnik
Bernd
B
D006801:Humans; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009154:Mutation; D009857:Oncogenes; D011973:Receptors, LDL / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D051176:beta Catenin / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; C510813:LRP10 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D051176:beta Catenin
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