Center for Molecular Medicine Cologne

Angelika A Noegel / Peter Nürnberg - C 11

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

Filippi syndrome (FS) and ectrodactyly ectodermal dysplasia without cleft lip/palate (EECWOCLP) are developmental disorders characterized by craniodigital and limb deformities, respectively. These disorders have received insufficient attention in the past. We identified disease-causing DNA variants in CSNK2B and LEF1 for FS and EEC-WOCLP, respectively. Functional analyses of variants identified in both genes deregulate Wnt signaling pathway, which plays the main role in disease pathogenesis of FS and EECWOCLP.


FS (MIM 272440) is a genetic disorder of cranio-digital abnormalities associated with short stature, microcephaly, characteristic face, syn­dactyly and intellectual disability as the major phenotypes. No molecular genetic cause of Filippi syndrome was known until we published that mutations in CKAP2L may cause FS. EEC-WOCLP(MIM 129810) presents with a split-hand/foot malformation (SHFM) accompanied by ectodermal anomalies like hypotrichosis and abnormal dentition.
To date, no molecular genetic cause of this disorder is known. Our ongoing genomic analyses led to the discovery of a second candidate gene of FS and a first one involved in EEC-WOCLP. We are investigating the functions of the cor­respondingproteins and found impaired Wnt signaling to be implicated in the etiology of both disorders.

Mutation of CSNK2B, the gene for casein kinase II subunit beta (CK2β), causes Filippi syndrome

The identified CSNK2B mutation (Fig. 1A) causes an up-regulation of CK2βat transcript and protein level with the consequence of an impaired cross talk between α and βsubunits of CK2 as revealed by depletion assay and microscale thermophoresis. Effects of the mutation were also observed in two crucial pathways, canonical Wnt signaling (CWS) and DNA damage response (DDR). In CWS, the mutation impairs the interaction of CK2β with DVL3 (Fig. 1B) and β-catenin (Fig. 1C, upper panel). Intriguingly, we also found accumulation of inactive β-catenin in the cytosol and absence of active β-catenin in the nuclei of mutant LCLs (Fig. 1C, lower panel), which indicates an impaired kinase activity of CK2. Using an ADP-Glo assay, we could show that the mutation prevented the phosphorylation ofβ-catenin. As to DDR, we saw elevated γH2AX in mutant LCLs that resulted in altered expression of downstream DNA damage regulators like 53BP1 and CHK1, finally directing cells towards apoptosis.
RNA-seq data confirmed the differential expression of transcripts involved in CWS (Fig. 1D ) and transcriptional regulation (Fig. 1E), DDR and immune response, suggesting that FS may be caused by dysregulation of CWS and DDR. Exome sequencing of new FS families identified compound heterozygous variants (c.908_909delAA; p.Lys303­Serfs*12 and c.906A>T;p.Leu302Phe) in CDKL2, the gene for cyclin-dependent kinase-like 2, which we are proposing as a new FS gene to be investigated.

Mutations inLEF1, encoding Lymphoid enhancer-binding factor 1 (LEF-1), cause EEC-WOCLP

Initially, we found a single mutation (p.M23dup) in a Yemeni family. By collaboration with other groups with patients showing a similar phenotype, we could raise the number of potentially causal LEF1 mutations to four (Fig. 2A and 2B). LEF1 encodes a protein of 399 amino acids and has an N-terminal β-catenin binding domain and a C-terminal SOX-TCF_HMG-box domain. Two of the identified mutations, p.M23dup and p.E45Q, are located in the β-catenin binding domain, which is highly conserved and essential for Wnt signaling. Interestingly, homozygous Lef1 knockout mice show absence of teeth, mammary gland and hairs, similar to the phenotype seen in our LEF1 patients but without limb deformities, whereas heterozygous mice do not show any phenotype at all. However, ablation of Lef1 along with Tcf1 mimics the limb defects seen in our LEF1 patients.
With pull-down assays, we could show an impaired interaction of p.M23dup LEF-1 with β-catenin (Fig. 2C). RNA-seq data corroborated that the Wnt/ β-catenin signaling pathway is impaired. Differential expression of downstream targets of the Wnt/ β-catenin signaling pathway as well as of members of the HOX gene family were observed (Fig. 2D). Both Wnt and HOX are crucial for embryonic devel­opment. Notably, WNT10B mutations are known to cause split-hand/foot malformation 6 while HOXC13 and HOXD13 were implicated in synpolydactyly/ brachydactyly and ectodermal dysplasia 9, respect­ively. We also saw a strong upregulation of LGR5. Intriguingly, overexpression of this regulator in chicken embryos had already been linked tolimb defective phenotypeslike ectopic cartilage, enlarge­ment of the bones and extra-skeletal pieces.


The analyses regarding CK2βand LEF-1 are adding 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. Further, this study will improve the diagnostics of the patients and provide a solid basis for genetic counseling of the affected families.

Selected publications

1. Capecchi, G. et al. (2018). CKAP2L mutation confirms the diagnosis of Filippi syndrome. Clin Genet. 93, 1109-1110.

2. Braun, D.A. et al. (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest. 128, 4313-4328.

3. Moawia, A. et al. (2017). Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 82, 562-577.

4. Ahmad, I. et al. (2017). Genetic heterogeneity in Pakista­ni microcephaly families revisited. Clin Genet. 92, 62-68.

5. Sukumaran, S.K. (2017) CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly. Mol Genet Genomics. 292, 365-383. 

6. Szczepanski, S. et al. (2016). A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family. Hum Genet. 135, 157-170.

7. Hussain, M.S. et al. (2014). Mutations in CKAP2L, the Human Ortholog of the Mouse Radmis Gene, Cause Filippi Syndrome. Am. J. Hum. Genet. 95, 622-632.

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Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Hohne W, Noegel AA, Al-Owain M, Hortnagel K, Stobe P, Baig SM, Nurnberg P, Alkuraya FS, Hahn A, and Hussain MS (2017). Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol 82, 562-77.

Neidhardt G, Becker A, Hauke J, Horvath J, Bogdanova Markov N, Heilmann-Heimbach S, Hellebrand H, Thiele H, Altmuller J, Nurnberg P, Meindl A, Rhiem K, Blumcke B, Wappenschmidt B, Schmutzler RK, and Hahnen E (2017a). The RAD51C exonic splice-site mutations c.404G>C and c.404G>T are associated with familial breast and ovarian cancer. Eur J Cancer Prev 26, 165-9.

Neidhardt G, Hauke J, Ramser J, Gross E, Gehrig A, Muller CR, Kahlert AK, Hackmann K, Honisch E, Niederacher D, Heilmann-Heimbach S, Franke A, Lieb W, Thiele H, Altmuller J, Nurnberg P, Klaschik K, Ernst C, Ditsch N, Jessen F, Ramirez A, Wappenschmidt B, Engel C, Rhiem K, Meindl A, Schmutzler RK, and Hahnen E (2017b). Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. JAMA Oncol 3, 1245-8.

Peche VS, Holak TA, Burgute BD, Kosmas K, Kale SP, Wunderlich FT, Elhamine F, Stehle R, Pfitzer G, Nohroudi K, Addicks K, Stockigt F, Schrickel JW, Gallinger J, Schleicher M, and Noegel AA (2017). Erratum to: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy. Cell Mol Life Sci 74, 4045.

Ralser DJ, Basmanav FBU, Tafazzoli A, Wititsuwannakul J, Delker S, Danda S, Thiele H, Wolf S, Busch M, Pulimood SA, Altmuller J, Nurnberg P, Lacombe D, Hillen U, Wenzel J, Frank J, Odermatt B, and Betz RC (2017). Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. Journal of Clinical Investigation 127, 1485-90.

Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaite Z, Wessel SR, Zlatanou A, Vernet A, von Kriegsheim A, Mottram RM, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Al Tala S, Alswaid A, Ahmed S, Al-Aama JY, Altmuller J, Al Balwi M, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nurnberg P, Percin EF, Peron A, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, Tomancak P, Yigit G, Taylor AM, Reijns MA, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, and Stewart GS (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet 49, 537-49.

Riessland M, Kaczmarek A, Schneider S, Swoboda KJ, Lohr H, Bradler C, Grysko V, Dimitriadi M, Hosseinibarkooie S, Torres-Benito L, Peters M, Upadhyay A, Biglari N, Krober S, Holker I, Garbes L, Gilissen C, Hoischen A, Nurnberg G, Nurnberg P, Walter M, Rigo F, Bennett CF, Kye MJ, Hart AC, Hammerschmidt M, Kloppenburg P, and Wirth B (2017). Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis. Am J Hum Genet 100, 297-315.

Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, Nurnberg P, Schultz MJ, Horn J, Cremer OL, Bonten MJ, Hinds CJ, Wong HR, Knight JC, van der Poll T, and consortium M (2017). Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 5, 816-26.

Sukumaran SK, Stumpf M, Salamon S, Ahmad I, Bhattacharya K, Fischer S, Muller R, Altmuller J, Budde B, Thiele H, Tariq M, Malik NA, Nurnberg P, Baig SM, Hussain MS, and Noegel AA (2017). CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly. Mol Genet Genomics 292, 365-83.

van Doormaal PTC, Ticozzi N, Weishaupt JH, Kenna K, Diekstra FP, Verde F, Andersen PM, Dekker AM, Tiloca C, Marroquin N, Overste DJ, Pensato V, Nurnberg P, Pulit SL, Schellevis RD, Calini D, Altmuller J, Francioli LC, Muller B, Castellotti B, Motameny S, Ratti A, Wolf J, Gellera C, Ludolph AC, van den Berg LH, Kubisch C, Landers JE, Veldink JH, Silani V, and Volk AE (2017). The role of de novo mutations in the development of amyotrophic lateral sclerosis. Hum Mutat 38, 1534-41.

van Vught LA, Scicluna BP, Wiewel MA, Hoogendijk AJ, Klein Klouwenberg PMC, Ong DSY, Cremer OL, Horn J, Franitza M, Toliat MR, Nurnberg P, Bonten MMJ, Schultz MJ, van der Poll T, and Consortium M (2017). Association of Gender With Outcome and Host Response in Critically Ill Sepsis Patients. Crit Care Med 45, 1854-62.

Weissbach S, Reinert MC, Altmuller J, Kratzner R, Thiele H, Rosenbaum T, Nurnberg P, and Gartner J (2017). A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy. Am J Med Genet A 173, 2803-7.

Former Funding Period 01/2017 - 12/2019

Information from this funding period will not be updated anymore. New research related information is available here.

CMMC Funding Period 1/2020-12/2022

Peter Nürnberg | Muhammad Sajid Hussain – C 12

Deciphering the role of C1orf131 – a novel nucleolar protein – in the etiology of intellectual disability and microcephaly

Publications - Angelika A Noegel

Link to PubMed

Prof. Dr. Peter Nürnberg CMMC Cologne
Prof. Dr. Peter Nürnberg

Cologne Center for Genomics

CMMC - PI - C 12

+49 221 478 96801

+49 221 478 96803

Cologne Center for Genomics

Weyertal 115 b

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Peter Nürnberg

Link to PubMed

Group Members

Muhammad Sajid Hussain (Research Associate)
Salem Alawbathani (Doctoral student)
Abu Bakar Moawia (Doctoral student)
Syeda Seema Waseem (Doctoral student)
Arwa Khayyat (Doctoral student)
Kathrin Schrage (Doctoral student)
Maria Iqbal (Doctoral student
Maria Asif (Doctoral student)
Martina Munck (technician)

Figure 1

Figure 2