Universität zu Köln

Sukumaran, Salil K., Stumpf, Maria, Salamon, Sarah, Ahmad, Ilyas, Bhattacharya, Kurchi, Fischer, Sarah ORCID: 0000-0001-6227-3950, Mueller, Rolf, Altmueller, Janine, Budde, Birgit, Thiele, Holger, Tariq, Muhammad ORCID: 0000-0002-5334-403X, Malik, Naveed Altaf, Nuernberg, Peter, Baig, Shahid Mahmood, Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809 and Noegel, Angelika A. (2017). CDK5RAP2 interaction with components of the Hippo signaling pathway may play a role in primary microcephaly. Mol. Genet. Genomics, 292 (2). S. 365 - 384. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1617-4623

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sukumaran, Salil K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stumpf, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Salamon, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmad, Ilyas UNSPECIFIED UNSPECIFIED UNSPECIFIED Bhattacharya, Kurchi UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Sarah UNSPECIFIED orcid.org/0000-0001-6227-3950 UNSPECIFIED Mueller, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Budde, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Tariq, Muhammad UNSPECIFIED orcid.org/0000-0002-5334-403X UNSPECIFIED Malik, Naveed Altaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Baig, Shahid Mahmood UNSPECIFIED UNSPECIFIED UNSPECIFIED Hussain, Muhammad Sajid UNSPECIFIED orcid.org/0000-0002-1353-8809 UNSPECIFIED Noegel, Angelika A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-235672
DOI:	10.1007/s00438-016-1277-x
Journal or Publication Title:	Mol. Genet. Genomics
Volume:	292
Number:	2
Page Range:	S. 365 - 384
Date:	2017
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1617-4623
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ORGAN SIZE CONTROL; CENTROSOME FUNCTION; PROTEIN; YAP; MUTATION; CELLS; DROSOPHILA; COMPLEX; TAZ; PROLIFERATION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23567