IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences1. An identity-by-descent analysis in a family with IMAGe syndrome2 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 progression3, 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 syndrome4.
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This work was funded by the Doris Duke Charitable Foundation and National Institute of Child Health and Human Development RO1HD068138. V.A.A. was supported by the US National Institutes of Health (NIH) 1 F31HD068136 training grant. The human embryonic and fetal material was provided by the Joint Medical Research Council (grant G0700089) and Wellcome Trust (grant GR082557) Human Developmental Biology Resource (www.hdbr.org). J.C.A. was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (079666). We thank R. Matera (NIH) for kindly providing the pCI-neo-(HA)3-human ubiquitin construct. We thank E.R.B. McCabe for initial crucial support of the adrenal research for E.V. and for providing one of the original IMAGe patient's DNA samples. We thank M. Le Merrer and C. Lecointre, who participated in the initial clinical description of IMAGe.
The authors declare no competing financial interests.
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Arboleda, V., Lee, H., Parnaik, R. et al. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 44, 788–792 (2012) doi:10.1038/ng.2275
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