Arboleda, V.A., Lee, H., Parnaik, R., Fleming, A., Banerjee, A., Ferraz-de-Souza, B., Délot, E.C., Rodriguez-Fernandez, I.A., Braslavsky, D., Bergadá, I., Dell'angelica, E.C., Nelson, S.F., Martinez-Agosto, J.A., Achermann, J.C., Vilain, E. (2012). Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.  Nat. Genet. 44(7): 788--792.

FBrf0218750

Research paper

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.

PMC3386373 (PMC) (EuropePMC)