title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
abstract: 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.
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Barbara
authors.initials: B
authors.lastname: Pawlik
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.forename: Mona
authors.initials: M
authors.lastname: Aglan
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.forename: Ferda
authors.initials: F
authors.lastname: Percin
authors.forename: Frances
authors.initials: F
authors.lastname: Goodman
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Asim
authors.initials: A
authors.lastname: Cenani
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.forename: Boi-Dinh
authors.initials: BD
authors.lastname: Chung
authors.forename: Samira
authors.initials: S
authors.lastname: Ismail
authors.forename: Khalda
authors.initials: K
authors.lastname: Amr
authors.forename: Ayca D
authors.initials: AD
authors.lastname: Aslanger
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
authors.forename: Pete
authors.initials: P
authors.lastname: Scambler
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Samia A
authors.initials: SA
authors.lastname: Temtamy
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: 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*
chemical_list: 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
references.citation: Am J Hum Genet. 2000 Jun;66(6):1945-57
references.pmid: 10796874
references.citation: Nat Genet. 2009 Jan;41(1):15-7
references.pmid: 19079262
references.citation: Genet Couns. 2000;11(1):41-7
references.pmid: 10756427
references.citation: Nature. 2000 Sep 28;407(6803):535-8
references.pmid: 11029008
references.citation: Nat Rev Genet. 2003 Feb;4(2):133-43
references.pmid: 12560810
references.citation: Cell. 2001 Nov 16;107(4):513-23
references.pmid: 11719191
references.citation: Genes Dev. 2003 Feb 1;17(3):394-409
references.pmid: 12569130
references.citation: Am J Hum Genet. 1998 Jul;63(1):259-66
references.pmid: 9634505
references.citation: Clin Dysmorphol. 2003 Apr;12(2):77-83
references.pmid: 12868467
references.citation: Cell. 2008 Oct 17;135(2):334-42
references.pmid: 18848351
references.citation: Clin Genet. 2001 Mar;59(3):203-5
references.pmid: 11260233
references.citation: Science. 2007 Mar 2;315(5816):1278-82
references.pmid: 17332414
references.citation: Bioinformatics. 2005 May 1;21(9):2123-5
references.pmid: 15647291
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: J Biol Chem. 2006 Aug 11;281(32):22429-33
references.pmid: 16793760
references.citation: Annu Rev Cell Dev Biol. 2001;17:87-132
references.pmid: 11687485
references.citation: Am J Hum Genet. 2008 Feb;82(2):464-76
references.pmid: 18252226
references.citation: Bioinformatics. 2005 Apr 15;21(8):1730-2
references.pmid: 15377505
references.citation: PLoS One. 2008;3(12):e4092
references.pmid: 19116665
references.citation: Nat Rev Genet. 2006 Nov;7(11):841-50
references.pmid: 17047684
references.citation: Am J Hum Genet. 2009 Aug;85(2):155-67
references.pmid: 19631309
references.citation: Genomics. 2006 Nov;88(5):600-9
references.pmid: 16963222
references.citation: Z Kinderheilkd. 1967;101(3):181-90
references.pmid: 4298043
references.citation: Am J Med Genet. 1997 Jun 27;70(4):341-5
references.pmid: 9182770
references.citation: Hum Mol Genet. 2005 Nov 15;14(22):3523-38
references.pmid: 16207730
references.citation: Genet Couns. 2003;14(3):313-9
references.pmid: 14577675
references.citation: Bioinformatics. 2001 Aug;17(8):742-3
references.pmid: 11524377
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: PLoS One. 2009 Nov 20;4(11):e7930
references.pmid: 19936252
references.citation: Clin Dysmorphol. 2008 Oct;17(4):269-70
references.pmid: 18978656