title: CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly.
abstract: Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in brain size but with normal architecture. It is often linked to mutations in genes coding for centrosomal proteins; however, their role in brain size regulation is not completely understood. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a novel mutation (XM_011518861.1; c.4114C > T) in CDK5RAP2, the gene associated with primary microcephaly-3 (MCPH3), leading to a premature stop codon (p.Arg1372*). CDK5RAP2 is a component of the pericentriolar material important for the microtubule-organizing function of the centrosome. Patient-derived primary fibroblasts had strongly decreased CDK5RAP2 amounts, showed centrosomal and nuclear abnormalities and exhibited changes in cell size and migration. We further identified an interaction of CDK5RAP2 with the Hippo pathway components MST1 kinase and the transcriptional regulator TAZ. This finding potentially provides a mechanism through which the Hippo pathway with its roles in the regulation of centrosome number is linked to the centrosome. In the patient fibroblasts, we observed higher levels of TAZ and YAP. However, common target genes of the Hippo pathway were downregulated as compared to the control with the exception of BIRC5 (Survivin), which was significantly upregulated. We propose that the centrosomal deficiencies and the altered cellular properties in the patient fibroblasts can also result from the observed changes in the Hippo pathway components which could thus be relevant for MCPH and play a role in brain size regulation and development.
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.
authors.forename: Salil K
authors.initials: SK
authors.lastname: Sukumaran
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Stumpf
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Salamon
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
authors.forename: Ilyas
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.
authors.forename: Kurchi
authors.initials: K
authors.lastname: Bhattacharya
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Budde
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tariq
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Naveed Altaf
authors.initials: NA
authors.lastname: Malik
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany. nuernberg@uni-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany. nuernberg@uni-koeln.de.|Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany. nuernberg@uni-koeln.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan. shahid_baig2002@yahoo.com.
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany.|Cologne Center for Genomics (CCG), University of Cologne, 50931, Cologne, Germany.
authors.forename: Muhammad Sajid
authors.initials: MS
authors.lastname: Hussain
authors.affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Köln, Germany. noegel@uni-koeln.de.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Köln, Germany. noegel@uni-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Köln, Germany. noegel@uni-koeln.de.
authors.forename: Angelika A
authors.initials: AA
authors.lastname: Noegel
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001921:Brain / Q000502:physiology; D018797:Cell Cycle Proteins; D002465:Cell Movement; D048429:Cell Size; D002478:Cells, Cultured; D018385:Centrosome / Q000648:ultrastructure; D018389:Codon, Nonsense; D004247:DNA / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D057809:HEK293 Cells; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009929:Organ Size; D010375:Pedigree; D010750:Phosphoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D004247:DNA; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Centrosome; Hippo pathway; MCPH; MST1; YAP/TAZ