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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Hyperplasia, Congenital / genetics*
  • Adrenal Hyperplasia, Congenital / metabolism
  • Adrenal Insufficiency
  • Animals
  • Beckwith-Wiedemann Syndrome / genetics
  • Beckwith-Wiedemann Syndrome / metabolism
  • Cell Line, Transformed
  • Chromosomes, Human, Pair 11
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism
  • Drosophila
  • Exons
  • Female
  • Fetal Growth Retardation / genetics*
  • Fetal Growth Retardation / metabolism
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Loci
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Humans
  • Hypoadrenocorticism, Familial
  • Male
  • Mutation*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / metabolism
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein Binding / genetics
  • Protein Structure, Tertiary / genetics

Substances

  • CDKN1C protein, human
  • Cyclin-Dependent Kinase Inhibitor p57
  • Proliferating Cell Nuclear Antigen

Supplementary concepts

  • Pyle disease