Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome.
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.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Valerie A
VA
Arboleda
Hane
H
Lee
Rahul
R
Parnaik
Alice
A
Fleming
Abhik
A
Banerjee
Bruno
B
Ferraz-de-Souza
Emmanuèle C
EC
Délot
Imilce A
IA
Rodriguez-Fernandez
Debora
D
Braslavsky
Ignacio
I
Bergadá
Esteban C
EC
Dell'Angelica
Stanley F
SF
Nelson
Julian A
JA
Martinez-Agosto
John C
JC
Achermann
Eric
E
Vilain
D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism; D000309:Adrenal Insufficiency; D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002880:Chromosomes, Human, Pair 11; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila; D005091:Exons; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D000075262:Hypoadrenocorticism, Familial; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018809:Proliferating Cell Nuclear Antigen