Journal
NATURE GENETICS
Volume 44, Issue 7, Pages 788-792Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2275
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Funding
- Doris Duke Charitable Foundation
- National Institute of Child Health and Human Development [RO1HD068138]
- US National Institutes of Health (NIH) [1 F31HD068136]
- Joint Medical Research Council [G0700089]
- Wellcome Trust [GR082557, 079666]
- MRC [G9900837, G0700089] Funding Source: UKRI
- Medical Research Council [G0700089, G9900837] Funding Source: researchfish
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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).
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