Angelika A Noegel / Peter Nürnberg - C 11

Role of Wnt signaling in the etiology of Filippi syndrome and ectrodactyly ectodermal dysplas

Abstract

Filippi syndrome (FS) and ectrodactyly ectodermal dysplasia without cleft lip/palate (EEC-WOCLP) are develpmental disorders characterized by craniodigital and limb deformities, respectively. These disorders have received insufficient attention in the past. Recently, we reported the first gene (CKAP2L) to be involved in FS. No underlying gene defect for EEC-WOCLP has been reported to date. Here, we suggest a second candidate gene (CSNK2B) for FS in which we identified a de novo mutation in an Italian family by whole-exome sequencing (WES). We also identified the first disease-causing DNA variant for autosomal recessive EEC-WOCLP. We found it using WES in a consanguineous family from Yemen. The affected gene codes for lymphoid enhancer-binding factor 1 (LEF-1). Both new candidate genes are functionally linked. CSNK2B encodes CK2ß, which is the regulatory subunit of protein kinase CK2, and CK2 and LEF-1 both play a role in Wnt signaling. This pathway is known to regulate craniofacial development whereupon CK2 regulates both LEF-1 and ß-catenin to enhance their binding affinity to each other and prevent LEF-1 to associate with TLE1, which is a negative regulator of Wnt signaling. We hypothesize that mutations of CSNK2B and LEF1 both impair Wnt/ß-catenin signaling events. We aim to unravel the consequences of this impairment and to gain new insight into the etiology of FS and EEC-WOCLP. To this end we will also explore further genetic causes of the two disorders in additional families already recruited (13 FS and 2 EEC-WOCLP) as well as to be ascertained during the project phase.

Clinical/medical relevance and sustainability in disease understanding

The planned analyses regarding CK2ß, LEF-1 and newly identified gene products which may be found to be functionally compromised by mutations in FS and EEC-WOCLP families will add important facts to the emerging network of the involved pathways. To understand these novel pathways will be instrumental for the development of a better treatment of these disorders. Futher, this study will improve the diagnostics of the patients and provide a solid basis for genetic counseling of affected families.


Prof. Dr. rer. nat. Angelika A Noegel

Institute for Biochemistry I

Prof. Dr. rer. nat. Angelika A Noegel

Principal Investigator C 11
Executive Board Member

noegel@uni-koeln.de

Work +49 221 478 6980

Fax (Work) +49 221 478 6979

Institute of Biochemistry I
Joseph-Stelzmann-Str. 52
50931 Cologne

http://www.uni-koeln.de/med-fak/biochemie/biomed1/

Publications - Angelika A Noegel

Link to PubMed


Prof. Dr. rer. nat. Peter Nürnberg

Cologne Center for Genomics (CCG)

Prof. Dr. rer. nat. Peter Nürnberg

Co-Principal Investigator C 11

nuernberg@uni-koeln.de

Work +49 221 478 96801

Fax (Work) +49 221 478 96803

Cologne Center for Genomics (CCG)
Weyertal 115 b
50931 Cologne

Publications - Peter Nürnberg

Link to PubMed