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LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome  Yun Li, Barbara Pawlik, Nursel Elcioglu,

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Presentation on theme: "LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome  Yun Li, Barbara Pawlik, Nursel Elcioglu,"— Presentation transcript:

1 LRP4 Mutations Alter Wnt/β-Catenin Signaling and Cause Limb and Kidney Malformations in Cenani-Lenz Syndrome  Yun Li, Barbara Pawlik, Nursel Elcioglu, Mona Aglan, Hülya Kayserili, Gökhan Yigit, Ferda Percin, Frances Goodman, Gudrun Nürnberg, Asim Cenani, Jill Urquhart, Boi-Dinh Chung, Samira Ismail, Khalda Amr, Ayca D. Aslanger, Christian Becker, Christian Netzer, Pete Scambler, Wafaa Eyaid, Hanan Hamamy, Jill Clayton-Smith, Raoul Hennekam, Peter Nürnberg, Joachim Herz, Samia A. Temtamy, Bernd Wollnik  The American Journal of Human Genetics  Volume 86, Issue 5, Pages (May 2010) DOI: /j.ajhg Copyright © 2010 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Clinical Findings in Families with CLS and Mapping of the CLS1 Locus (A) Typical hand and feet anomalies seen in CLS patients. (B) Graphical view of additive LOD-score calculations of genome-wide SNP mapping in families CL-1 to CL-6. Ideogram of chromosome 11 showing the localization of linked region. (C) Haplotypes of CLS families included in the initial linkage analysis. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Mutations Identified in LRP4
(A) Electropherograms of identified homozygous LRP4 mutations compared with heterozygous carrier and WT sequences (n.a., not available). (B) Electropherograms of identified compound-heterozygous splice-site mutations in LRP4 causing aberrant splicing and premature protein truncation. (C) Schematic view of LRP4 receptor domains and localization of identified CLS mutations. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Additional CLS Families and Genetic Heterogeneity
(A) Pedigrees of additional CLS families. (B) The LRP4 locus was excluded in families CL-13 and CL-14 by haplotype analysis. (C and D) Identification of an LRP4 founder mutation, p.D529N, in three Turkish CLS families (C) and of p.D137N in two families from Egypt (D). Identical haplotypes are shown in red. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Splicing Effects of Mutations in Family CL-11
(A) Analysis of the heterozygous c.200-9G>A mutation. cDNA sequences of the exon 2-exon 3 boundary of wild-type (wt) and patient cDNA are shown (without [P_cDNA] and after subcloning via the TOPO-Vector system [P_cDNA_topo]). (B) Analysis of the heterozygous c.4959G>C mutation. Electropherograms show the cDNA sequences of LRP4 transcripts encoded by exon 33 to exon 35 of wild-type (wt), and skipping of exon 34 in the patient cDNA. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Functional Analysis of LRP4 Missense Mutations
(A) Results from the Dual Luciferase Reporter Assay after coexpression of LRP6, WNT1, and wild-type and mutant LRP4 in different combinations. Graph depicting the relative Luciferase activities (mean and standard deviations of six experiments, in triplicate each time). Comparable steady-state expression levels of wild-type and mutant LRP4 proteins are shown by immunoblotting of total lysates after measurement of luciferase activity. (B) Compared to wild-type LRP4 and wild-type insulin receptor (IR), mutant LRP4 proteins are not detectable by cell-surface biotinylation. Results from three independent experiments are shown. (C) Schematic representation of LRP4 function in LRP6-mediated activation of Wnt/β-catenin signaling. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

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