RGD Reference Report - Mutations in CDK5RAP2 cause Seckel syndrome. - Rat Genome Database

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Mutations in CDK5RAP2 cause Seckel syndrome.

Authors: Yigit, Gökhan  Brown, Karen E  Kayserili, Hülya  Pohl, Esther  Caliebe, Almuth  Zahnleiter, Diana  Rosser, Elisabeth  Bögershausen, Nina  Uyguner, Zehra Oya  Altunoglu, Umut  Nürnberg, Gudrun  Nürnberg, Peter  Rauch, Anita  Li, Yun  Thiel, Christian Thomas  Wollnik, Bernd 
Citation: Yigit G, etal., Mol Genet Genomic Med. 2015 Sep;3(5):467-80. doi: 10.1002/mgg3.158. Epub 2015 May 24.
RGD ID: 13450906
Pubmed: PMID:26436113   (View Abstract at PubMed)
PMCID: PMC4585455   (View Article at PubMed Central)
DOI: DOI:10.1002/mgg3.158   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
microcephaly  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
microcephaly  ISOCDK5RAP2 (Homo sapiens)13450906; 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Seckel syndrome  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Seckel syndrome  ISOCDK5RAP2 (Homo sapiens)13450906; 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Convex nasal ridge  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Delayed skeletal maturation  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
High, narrow palate  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Intellectual disability  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Micrognathia  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Sloping forehead  IAGP 13450906DNA:mutations:splice junction:c.383+1G>C and c.4005-9A>G(human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cdk5rap2  (CDK5 regulatory subunit associated protein 2)

Genes (Mus musculus)
Cdk5rap2  (CDK5 regulatory subunit associated protein 2)

Genes (Homo sapiens)
CDK5RAP2  (CDK5 regulatory subunit associated protein 2)


Additional Information