Mutations in CDK5RAP2 cause Seckel syndrome

This study establishes CDK5RAP2 as a disease‐causing gene for Seckel syndrome and shows that CDK5RAP2 deficiency results in severe defects in mitosis and spindle organization. AbstractSeckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice ‐site mutations c.383+1G>C and c.4005 ‐9A>G inCDK5RAP2 in two consanguineous families with Seckel syndrome.CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establishCDK5RAP2 as a disease ‐causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of t he disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations inCDK5RAP2 andCEP152. This finding points toward a potential additive genetic effect of mutations inCDK5RAP2 andCEP152.

Source: Molecular Genetics & Genomic Medicine - September 15, 2015 Category: Genetics & Stem Cells Authors: G ökhan Yigit, Karen E. Brown, Hülya Kayserili, Esther Pohl, Almuth Caliebe, Diana Zahnleiter, Elisabeth Rosser, Nina Bögershausen, Zehra Oya Uyguner, Umut Altunoglu, Gudrun Nürnberg, Peter Nürnberg, Anita Rauch, Yun Li, Christian Thoma Tags: Original Article Source Type: research