LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome

被引：133

作者：

Li, Yun ^{[1
,2
]}

Pawlik, Barbara ^{[1
,2
]}

Elcioglu, Nursel ^{[3
]}

Aglan, Mona ^{[4
,5
]}

Kayserili, Huelya ^{[6
]}

Yigit, Goekhan ^{[1
,2
]}

Percin, Ferda ^{[7
]}

Goodman, Frances ^{[8
]}

Nuernberg, Gudrun ^{[1
,9
,10
]}

Cenani, Asim ^{[11
]}

Urquhart, Jill ^{[12
]}

Chung, Boi-Dinh ^{[2
,10
]}

Ismail, Samira ^{[4
,5
]}

Amr, Khalda ^{[4
,5
]}

Aslanger, Ayca D. ^{[6
]}

Becker, Christian ^{[9
,10
]}

Netzer, Christian ^{[1
,2
,10
]}

Scambler, Pete ^{[13
]}

Eyaid, Wafaa ^{[14
]}

Hamamy, Hanan ^{[15
]}

Clayton-Smith, Jill ^{[12
]}

Hennekam, Raoul ^{[8
,16
]}

Nuernberg, Peter ^{[1
,9
,10
,17
]}

Herz, Joachim ^{[18
]}

Temtamy, Samia A. ^{[4
,5
]}

Wollnik, Bernd ^{[1
,2
,17
]}

机构：

[1] Univ Cologne, CMMC, D-50931 Cologne, Germany

[2] Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany

[3] Marmara Univ Hosp, Dept Pediat Genet, TR-34668 Istanbul, Turkey

[4] Natl Res Ctr, Div Human Genet & Genome Res, Dept Clin, Cairo 12311, Egypt

[5] Natl Res Ctr, Div Human Genet & Genome Res, Dept Mol Genet, Cairo 12311, Egypt

[6] Istanbul Univ, Istanbul Fac Med, Dept Med Genet, TR-34094 Istanbul, Turkey

[7] Gazi Univ, Fac Med, Dept Med Genet, TR-06500 Ankara, Turkey

[8] UCL, Great Ormond St Hosp Children, Inst Child Hlth, Clin & Mol Genet Unit, London WC1N 3JH, England

[9] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[10] Univ Cologne, Inst Genet, D-50674 Cologne, Germany

[11] Istanbul Univ, Cerrahpasa Med Sch, GETAM, TR-34452 Istanbul, Turkey

[12] St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester M13 0JH, Lancs, England

[13] Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England

[14] King Abdul Aziz Med City, King Fahad Natl Guard Hosp, Dept Pediat, Riyadh 11426, Saudi Arabia

[15] Univ Hosp Geneva, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[16] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands

[17] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50674 Cologne, Germany

[18] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2010年 / 86卷 / 05期

基金：

美国国家卫生研究院;

关键词：

FACIAL DYSMORPHISM; RENAL HYPOPLASIA; LINKAGE ANALYSIS; RECEPTOR; PATHWAYS; COMPLEX; MODELS; FAMILY; TOOL;

D O I：

10.1016/j.ajhg.2010.03.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：696 / 706

页数：11

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