Mutations in the PCNA-binding domain of CDKNIC vause IMAGe syndrome

ARBOLEDA VA; LEE H; PARNAIK R; FLEMING A; BANERJEE A; FERRAZ-DE-SOUZA B; DÉLOT EC; RODRIGUEZ-FERNANDEZ IA; BRASLAVSKY D; BERGADÁ I; DELL'ANGELICA EC; NELSON SF; MARTINEZ-AGOSTO JA; ACHERMANN JC; VILAIN E

NATURE GENETICS

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2012 p. 788 - 792

1061-4036

IMAGE Syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) is an undergrowth developmental disorder with life-threatening consequences1. Identity-by-descent analysis in a family with IMAGE syndrome2 identified a 17.2 megabase (Mb) locus on 11p15 that segregated in affected family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in syndrome2 identified a 17.2 megabase (Mb) locus on 11p15 that segregated in affected family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in 1. Identity-by-descent analysis in a family with IMAGE syndrome2 identified a 17.2 megabase (Mb) locus on 11p15 that segregated in affected family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in 2 identified a 17.2 megabase (Mb) locus on 11p15 that segregated in affected family members. Targeted exon array capture of the disease locus, followed by highthroughput genomic sequencing and validated by dideoxysequencing, identified missense mutations in imprinted gene CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in CDKN1C (P57KIP2) in two familial and four unrelated patients. Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGE syndrome. CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in progression3 and targeted expression of IMAGE-associated CDKN1C mutations in CDKN1C inhibits cellcycle progression3 and targeted expression of IMAGE-associated CDKN1C mutations in3 and 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 gain-of-function mechanism. All IMAGE-associated mutations clustered in the PCNA caused severe eye growth defects compared to wild type CDKN1C, suggesting a gain-of-function mechanism. All IMAGE-associated mutations clustered in the PCNA