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

• Published in: Nature genetics Vol. 44; no. 7; pp. 788 - 792
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2012; Nature Publishing Group
• Subjects: 631/136; 631/208/2489/144; Adrenal Hyperplasia, Congenital - genetics; Adrenal Hyperplasia, Congenital - metabolism; Adrenal Insufficiency; Agriculture; Animal Genetics and Genomics; Animals; Beckwith-Wiedemann Syndrome - genetics; Beckwith-Wiedemann Syndrome - metabolism; Binding sites; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Transformed; Charitable foundations; Chromosomes, Human, Pair 11; Complex syndromes; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Cyclin-Dependent Kinase Inhibitor p57 - metabolism; Deoxyribonucleic acid; Design; DNA; Drosophila; Exons; Experiments; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Fetus; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genes; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - metabolism; Genetic Loci; Genetic Predisposition to Disease; Genetic testing; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Growth retardation; Health aspects; HEK293 Cells; Human Genetics; Humans; Hypoadrenocorticism, Familial; Insects; letter; Male; Medical genetics; Medical sciences; Mutation; Osteochondrodysplasias - genetics; Osteochondrodysplasias - metabolism; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Protein Binding - genetics; Protein Structure, Tertiary - genetics; Proteins; United States; United Kingdom; Syndrome; Mutation
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2275

Eric Vilain and colleagues identify missense mutations in the imprinted gene CDKN1C , encoding the p57KIP2 cyclin dependent kinase inhibitor, in individuals with IMAGe syndrome. IMAGe syndrome is a developmental disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies. 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 .