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

作者：Arboleda Valerie A; Lee Hane; Parnaik Rahul; Fleming Alice; Banerjee Abhik; Ferraz de Souza Bruno; Delot Emmanuele C; Rodriguez Fernandez Imilce A; Braslavsky Debora; Bergada Ignacio; Dell'Angelica Esteban C; Nelson Stanley F; Martinez Agosto Julian A; Achermann John C; Vilain Eric^*

来源：Nature Genetics, 2012, 44(7): 788-792.

DOI：10.1038/ng.2275

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences(1). An identity-by-descent analysis in a family with IMAGe syndrome(2) 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(3), 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(4).

• 出版日期2012-7