Abstract
Seckel 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 in CDK5RAP2 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 establish CDK5RAP2 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 the 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 in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.
Highlights
Seckel syndrome (MIM 210600 for SCKL1) is an autosomal recessive disorder characterized by intrauterine growth retardation, proportionate short stature, severe microcephaly, intellectual disability, and a typical facial appearance with a prominent and beaked nose, sloping forehead, and micrognathia (Seckel 1960; Majewski et al 1982a)
The human CDK5RAP2 protein consists of 1,893 amino acids and contains several coiled-coil domains as well as two structural maintenance-of-chromosomes (SMC) domains that are known to be important for chromatid cohesion and DNA recombination during mitosis (25 and references therein)
Direct protein interaction with CDK5R1 and pericentrin is mainly effected via the C-terminal region, whereas binding to the c-tubulin ring complex (c-TuRC) and thereby its recruitment to centrosomes occurs via the N-terminal region (Fong et al 2008; Wang et al 2010)
Summary
Seckel syndrome (MIM 210600 for SCKL1) is an autosomal recessive disorder characterized by intrauterine growth retardation, proportionate short stature, severe microcephaly, intellectual disability, and a typical facial appearance with a prominent and beaked nose, sloping forehead, and micrognathia (Seckel 1960; Majewski et al 1982a). Intellectual disability is associated with variable structural brain anomalies, and this combination mainly distinguishes Seckel syndrome from an overlapping primordial dwarfism syndrome known as microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) (Hall et al 2004; Willems et al 2010). Seckel syndrome is a genetically heterogeneous disorder; autosomal recessive mutations in eight different genes have been identified to date. They include very a 2015 The Authors.
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