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- Title
Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
- Authors
Arboleda, Valerie A; Lee, Hane; Parnaik, Rahul; Fleming, Alice; Banerjee, Abhik; Ferraz-de-Souza, Bruno; Délot, Emmanuèle C; Rodriguez-Fernandez, Imilce A; Braslavsky, Debora; Bergadá, Ignacio; Dell'Angelica, Esteban C; Nelson, Stanley F; Martinez-Agosto, Julian A; Achermann, John C; Vilain, Eric
- Abstract
IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.
- Publication
Nature genetics, 2012, Vol 44, Issue 7, p788
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.2275