Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

VA Arboleda, H Lee, R Parnaik, A Fleming… - Nature …, 2012 - nature.com
VA Arboleda, H Lee, R Parnaik, A Fleming, A Banerjee, B Ferraz-de-Souza, EC Délot…
Nature genetics, 2012nature.com
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 …
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.
nature.com