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.

Introduction

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.

Perspectives

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.

Bustos, B.I., Perez-Palma, E., Buch, S., Azocar, L., Riveras, E., Ugarte, G.D., Toliat, M., Nurnberg, P., Lieb, W., Franke, A., Hinz, S., Burmeister, G., von Schonfels, W., Schafmayer, C., Volzke, H., Volker, U., Homuth, G., Lerch, M.M., Santos, J.L., Puschel, K., Bambs, C., Roa, J.C., Gutierrez, R.A., Hampe, J., De Ferrari, G.V., and Miquel, J.F. (2019). Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry. Scientific Reports 9.

Kinfe, T.M., Asif, M., Chakravarthy, K.V., Deer, T.R., Kramer, J.M., Yearwood, T.L., Hurlemann, R., Hussain, M.S., Motameny, S., Wagle, P., Nurnberg, P., Gravius, S., Randau, T., Gravius, N., Chaudhry, S.R., and Muhammad, S. (2019). Unilateral L4-dorsal root ganglion stimulation evokes pain relief in chronic neuropathic postsurgical knee pain and changes of inflammatory markers: part II whole transcriptome profiling. Journal of Translational Medicine 17.

Perlee, D., de Vos, A.F., Scicluna, B.P., Mancheno, P., De la Rosa, O., Dalemans, W., Nurnberg, P., Lombardo, E., and Van der Poll, T. (2019). Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae. Stem Cells Translational Medicine 8, 785-96.

Wagener, R., Seufert, J., Raimondi, F., Bens, S., Kleinheinz, K., Nagel, I., Altmuller, J., Thiele, H., Hubschmann, D., Kohler, C.W., Nurnberg, P., Au-Yeung, R., Burkhardt, B., Horn, H., Leoncini, L., Jaffe, E.S., Ott, G., Rymkiewicz, G., Schlesner, M., Russell, R.B., Klapper, W., and Siebert, R. (2019). The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 133, 962-6.

Weber-Lassalle, N., Borde, J., Weber-Lassalle, K., Horvath, J., Niederacher, D., Arnold, N., Kaulfuss, S., Ernst, C., Paul, V.G., Honisch, E., Klaschik, K., Volk, A.E., Kubisch, C., Rapp, S., Lichey, N., Altmuller, J., Lepkes, L., Pohl-Rescigno, E., Thiele, H., Nurnberg, P., Larsen, M., Richters, L., Rhiem, K., Wappenschmidt, B., Engel, C., Meindl, A., Schmutzler, R.K., Hahnen, E., and Hauke, J. (2019). Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer. Breast Cancer Research 21.

Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, Volland R, Menon R, Heuckmann JM, Gartlgruber M, Hartlieb S, Henrich KO, Okonechnikov K, Altmuller J, Nurnberg P, Lefever S, de Wilde B, Sand F, Ikram F, Rosswog C, Fischer J, Theissen J, Hertwig F, Singhi AD, Simon T, Vogel W, Perner S, Krug B, Schmidt M, Rahmann S, Achter V, Lang U, Vokuhl C, Ortmann M, Buttner R, Eggert A, Speleman F, O'Sullivan RJ, Thomas RK, Berthold F, Vandesompele J, Schramm A, Westermann F, Schulte JH, Peifer M, and Fischer M (2018). A mechanistic classification of clinical phenotypes in neuroblastoma. Science 362, 1165-1170.

Alawbathani S, Kawalia A, Karakaya M, Altmuller J, Nurnberg P, and Cirak S (2018). Late diagnosis of a truncating WISP3 mutation entails a severe phenotype of progressive pseudorheumatoid dysplasia. Cold Spring Harb Mol Case Stud 4.

Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M, Hussain MS, Daga A, Widmeier E, Rao J, Ashraf S, Tan W, Lusk CP, Kolb A, Jobst-Schwan T, Schmidt JM, Hoogstraten CA, Eddy K, Kitzler TM, Shril S, Moawia A, Schrage K, Khayyat AIA, Lawson JA, Gee HY, Warejko JK, Hermle T, Majmundar AJ, Hugo H, Budde B, Motameny S, Altmuller J, Noegel AA, Fathy HM, Gale DP, Waseem SS, Khan A, Kerecuk L, Hashmi S, Mohebbi N, Ettenger R, Serdaroglu E, Alhasan KA, Hashem M, Goncalves S, Ariceta G, Ubetagoyena M, Antonin W, Baig SM, Alkuraya FS, Shen Q, Xu H, Antignac C, Lifton RP, Mane S, Nurnberg P, Khokha MK, and Hildebrandt F (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest 128, 4313-4328.

Broekaert IJ, Becker K, Gottschalk I, Korber F, Dotsch J, Thiele H, Altmuller J, Nurnberg P, Hunseler C, and Cirak S (2018). Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy. J Med Genet 10.1136/jmedgenet-2018-105262.

Eisenberger T, Di Donato N, Decker C, Delle Vedove A, Neuhaus C, Nurnberg G, Toliat M, Nurnberg P, Murbe D, and Bolz HJ (2018). A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73. Genet Med 20, 614-621.

Fazeli W, Becker K, Herkenrath P, Duchting C, Korber F, Landgraf P, Nurnberg P, Altmuller J, Thiele H, Koy A, Liebau MC, Simon T, Dotsch J, and Cirak S (2018). Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development. Neuropediatrics 10.1055/s-0038-1668141.

George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, and Thomas RK (2018). Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9, 1048.

Ghosh SG, Becker K, Huang H, Dixon-Salazar T, Chai G, Salpietro V, Al-Gazali L, Waisfisz Q, Wang H, Vaux KK, Stanley V, Manole A, Akpulat U, Weiss MM, Efthymiou S, Hanna MG, Minetti C, Striano P, Pisciotta L, De Grandis E, Altmuller J, Nurnberg P, Thiele H, Yis U, Okur TD, Polat AI, Amiri N, Doosti M, Karimani EG, Toosi MB, Haddad G, Karakaya M, Wirth B, van Hagen JM, Wolf NI, Maroofian R, Houlden H, Cirak S, and Gleeson JG (2018). Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome. Am J Hum Genet 103, 826.

Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmuller J, Nurnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schafer SC, Buttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, and Peifer M (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 9, 727.

Jabbari K, Bobbili DR, Lal D, Reinthaler EM, Schubert J, Wolking S, Sinha V, Motameny S, Thiele H, Kawalia A, Altmuller J, Toliat MR, Kraaij R, van Rooij J, Uitterlinden AG, Ikram MA, Euro ECC, Zara F, Lehesjoki AE, Krause R, Zimprich F, Sander T, Neubauer BA, May P, Lerche H, and Nurnberg P (2018). Rare gene deletions in genetic generalized and Rolandic epilepsies. PLoS One 13, e0202022.

Karakaya M, Storbeck M, Strathmann EA, Delle Vedove A, Holker I, Altmueller J, Naghiyeva L, Schmitz-Steinkruger L, Vezyroglou K, Motameny S, Alawbathani S, Thiele H, Polat AI, Okur D, Boostani R, Karimiani EG, Wunderlich G, Ardicli D, Topaloglu H, Kirschner J, Schrank B, Maroofian R, Magnusson O, Yis U, Nurnberg P, Heller R, and Wirth B (2018). Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Hum Mutat 39, 1284-1298.

Karakaya M, Storbeck M, Strathmann EA, Vedove AD, Holker I, Altmueller J, Naghiyeva L, Schmitz-Steinkruger L, Vezyroglou K, Motameny S, Alawbathani S, Thiele H, Polat AI, Okur D, Boostani R, Karimiani EG, Wunderlich G, Ardicli D, Topaloglu H, Kirschner J, Schrank B, Maroofian R, Magnusson O, Yis U, Nurnberg P, Heller R, and Wirth B (2018). Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Hum Mutat 10.1002/humu.23560.

Khan AO, Budde BS, Nurnberg P, Kawalia A, Lenzner S, and Bolz HJ (2018). Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype. Clin Genet 93, 149-154.

Lessel D, Ozel AB, Campbell SE, Saadi A, Arlt MF, McSweeney KM, Plaiasu V, Szakszon K, Szollos A, Rusu C, Rojas AJ, Lopez-Valdez J, Thiele H, Nurnberg P, Nickerson DA, Bamshad MJ, Li JZ, Kubisch C, Glover TW, and Gordon LB (2018). Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Hum Genet 137, 921-939.

Macheleidt IF, Dalvi PS, Lim SY, Meemboor S, Meder L, Kasgen O, Muller M, Kleemann K, Wang L, Nurnberg P, Russeler V, Schafer SC, Mahabir E, Buttner R, and Odenthal M (2018). Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol Oncol 12, 1965-1979.

Mross C, Marko M, Munck M, Glockner G, Motameny S, Altmuller J, Noegel AA, Eichinger L, Peche VS, and Neumann S (2018). Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice. Nucleus 9, 503-515.

Muller R, Stumpf M, Wehrstedt R, Sukumaran SK, Karow MA, Marko M, Noegel AA, and Eichinger L (2018). The regulatory subunit phr2AB of Dictyostelium discoideum phosphatase PP2A interacts with the centrosomal protein CEP161, a CDK5RAP2 ortholog. Genes Cells 23, 923-931.

Niestroj LM, Du J, Nothnagel M, May P, Palotie A, Daly MJ, Nurnberg P, Blumcke I, and Lal D (2018). Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies. Epilepsia 59, 2145-2152.

Pauli S, Altmuller J, Schroder S, Ohlenbusch A, Dreha-Kulaczewski S, Bergmann C, Nurnberg P, Thiele H, Li Y, Wollnik B, and Brockmann K (2018). Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. J Med Genet 10.1136/jmedgenet-2018-105470.

Romano MT, Tafazzoli A, Mattern M, Sivalingam S, Wolf S, Rupp A, Thiele H, Altmuller J, Nurnberg P, Ellwanger J, Gambon R, Baumer A, Kohlschmidt N, Metze D, Holdenrieder S, Paus R, Lutjohann D, Frank J, Geyer M, Bertolini M, Kokordelis P, and Betz RC (2018). Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am J Hum Genet 103, 777-785.

Schrader A, Crispatzu G, Oberbeck S, Mayer P, Putzer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmuller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brummendorf TH, Nurnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, and Herling M (2018). Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 9, 697.

Wagener R, Lopez C, Kleinheinz K, Bausinger J, Aukema SM, Nagel I, Toprak UH, Seufert J, Altmuller J, Thiele H, Schneider C, Kolarova J, Park J, Hubschmann D, Murga Penas EM, Drexler HG, Attarbaschi A, Hovland R, Kjeldsen E, Kneba M, Kontny U, de Leval L, Nurnberg P, Oschlies I, Oscier D, Schlegelberger B, Stilgenbauer S, Wossmann W, Schlesner M, Burkhardt B, Klapper W, Jaffe ES, Kuppers R, and Siebert R (2018). IG-MYC-positive neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas. Blood 10.1182/blood-2018-03-842088.

Zirkel A, Nikolic M, Sofiadis K, Mallm JP, Brackley CA, Gothe H, Drechsel O, Becker C, Altmuller J, Josipovic N, Georgomanolis T, Brant L, Franzen J, Koker M, Gusmao EG, Costa IG, Ullrich RT, Wagner W, Roukos V, Nurnberg P, Marenduzzo D, Rippe K, and Papantonis A (2018). HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. Mol Cell 70, 730-744 e736.

Ahmad I, Baig SM, Abdulkareem AR, Hussain MS, Sur I, Toliat MR, Nurnberg G, Dalibor N, Moawia A, Waseem SS, Asif M, Nagra H, Sher M, Khan MMA, Hassan I, Rehman SU, Thiele H, Altmuller J, Noegel AA, and Nurnberg P (2017). Genetic heterogeneity in Pakistani microcephaly families revisited. Clin Genet 92, 62-8.

Crispatzu G, Kulkarni P, Toliat MR, Nurnberg P, Herling M, Herling CD, and Frommolt P (2017). Semi-automated cancer genome analysis using high-performance computing. Hum Mutat 38, 1325-35.

Ehmke N, Graul-Neumann L, Smorag L, Koenig R, Segebrecht L, Magoulas P, Scaglia F, Kilic E, Hennig AF, Adolphs N, Saha N, Fauler B, Kalscheuer VM, Hennig F, Altmuller J, Netzer C, Thiele H, Nurnberg P, Yigit G, Jager M, Hecht J, Kruger U, Mielke T, Krawitz PM, Horn D, Schuelke M, Mundlos S, Bacino CA, Bonnen PE, Wollnik B, Fischer-Zirnsak B, and Kornak U (2017). De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. Am J Hum Genet 101, 833-43.

Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, Yoshiura KI, Oufadem M, Beck TJ, McGowan R, Magee AC, Altmuller J, Dion C, Thiele H, Gurzau AD, Nurnberg P, Meschede D, Muhlbauer W, Okamoto N, Varghese V, Irving R, Sigaudy S, Williams D, Ahmed SF, Bonnard C, Kong MK, Ratbi I, Fejjal N, Fikri M, Elalaoui SC, Reigstad H, Bole-Feysot C, Nitschke P, Ragge N, Levy N, Tuncbilek G, Teo AS, Cunningham ML, Sefiani A, Kayserili H, Murphy JM, Chatdokmaiprai C, Hillmer AM, Wattanasirichaigoon D, Lyonnet S, Magdinier F, Javed A, Blewitt ME, Amiel J, Wollnik B, and Reversade B (2017). De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet 49, 249-55.

Haliloglu G, Becker K, Temucin C, Talim B, Kucuksahin N, Pergande M, Motameny S, Nurnberg P, Aydingoz U, Topaloglu H, and Cirak S (2017). Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects. J Hum Genet 62, 497-501.

Harter P, Hauke J, Heitz F, Reuss A, Kommoss S, Marme F, Heimbach A, Prieske K, Richters L, Burges A, Neidhardt G, de Gregorio N, El-Balat A, Hilpert F, Meier W, Kimmig R, Kast K, Sehouli J, Baumann K, Jackisch C, Park-Simon TW, Hanker L, Krober S, Pfisterer J, Gevensleben H, Schnelzer A, Dietrich D, Neunhoffer T, Krockenberger M, Brucker SY, Nurnberg P, Thiele H, Altmuller J, Lamla J, Elser G, du Bois A, Hahnen E, and Schmutzler R (2017). Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One 12, e0186043.

Horpaopan S, Kirfel J, Peters S, Kloth M, Huneburg R, Altmuller J, Drichel D, Odenthal M, Kristiansen G, Strassburg C, Nattermann J, Hoffmann P, Nurnberg P, Buttner R, Thiele H, Kahl P, Spier I, and Aretz S (2017). Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS). Hered Cancer Clin Pract 15, 22.

Huppke P, Weissbach S, Church JA, Schnur R, Krusen M, Dreha-Kulaczewski S, Kuhn-Velten WN, Wolf A, Huppke B, Millan F, Begtrup A, Almusafri F, Thiele H, Altmuller J, Nurnberg P, Muller M, and Gartner J (2017). Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat Commun 8, 818.

Khan AO, Becirovic E, Betz C, Neuhaus C, Altmuller J, Maria Riedmayr L, Motameny S, Nurnberg G, Nurnberg P, and Bolz HJ (2017a). A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula. Sci Rep 7, 1411.

Khan AO, Budde BS, Nurnberg P, Kawalia A, Lenzner S, and Bolz HJ (2017b). Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype. Clin Genet 10.1111/cge.13022.

Lessel D, Wu D, Trujillo C, Ramezani T, Lessel I, Alwasiyah MK, Saha B, Hisama FM, Rading K, Goebel I, Schutz P, Speit G, Hogel J, Thiele H, Nurnberg G, Nurnberg P, Hammerschmidt M, Zhu Y, Tong DR, Katz C, Martin GM, Oshima J, Prives C, and Kubisch C (2017). Dysfunction of the MDM2/p53 axis is linked to premature aging. J Clin Invest 127, 3598-608.

Li P, Stumpf M, Muller R, Eichinger L, Glockner G, and Noegel AA (2017). The function of the inner nuclear envelope protein SUN1 in mRNA export is regulated by phosphorylation. Sci Rep 7, 9157.

Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmuller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brustle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schols L, Nurnberg P, Zuchner S, Klockgether T, Ramirez A, and Schule R (2017). Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain 140, 1561-78.

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.

Prof. Dr. Angelika A Noegel CMMC Cologne
Prof. Dr. Angelika A Noegel

Institute for Biochemistry I

Principal Investigator C 11

+49 221 478 6980

+49 221 478 6979

Institute for Biochemistry I

Joseph-Stelzmann-Str. 52

50931 Cologne

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

CMMC Profile Page

Curriculum Vitae (CV)

Publications - Angelika A Noegel

Link to PubMed

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

Cologne Center for Genomics (CCG)

Co-Principal Investigator C 11

+49 221 478 96801

+49 221 478 96803

Cologne Center for Genomics (CCG)

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