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Nat Genet. 2012 May 27;44(7):788-92. doi: 10.1038/ng.2275.

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

Author information

  • 1Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

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.

Comment in

  • Gain of function in CDKN1C. [Nat Genet. 2012]
PMID:
22634751
[PubMed - indexed for MEDLINE]
PMCID:
PMC3386373
Free PMC Article

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