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Open Access Publications from the University of California

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

  • Author(s): Arboleda, Valerie A
  • Lee, Hane
  • Parnaik, Rahul
  • Fleming, Alice
  • Banerjee, Abhik
  • Ferraz-de-Souza, Bruno
  • Délot, Emmanuèle C
  • Rodriguez-Fernandez, Imilce A
  • Braslavsky, Debora
  • Bergadá, Ignacio
  • Dell'Angelica, Esteban C
  • Nelson, Stanley F
  • Martinez-Agosto, Julian A
  • Achermann, John C
  • Vilain, Eric
  • et al.

Published Web Location

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.

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