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.
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Authors | Valerie A Arboleda, Hane Lee, Rahul Parnaik, Alice Fleming, Abhik Banerjee, Bruno Ferraz-de-Souza, Emmanuèle C Délot, Imilce A Rodriguez-Fernandez, Debora Braslavsky, Ignacio Bergadá, Esteban C Dell'Angelica, Stanley F Nelson, Julian A Martinez-Agosto, John C Achermann, Eric Vilain |
Journal | Nature genetics
(Nat Genet)
Vol. 44
Issue 7
Pg. 788-92
(May 27 2012)
ISSN: 1546-1718 [Electronic] United States |
PMID | 22634751
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- CDKN1C protein, human
- Cyclin-Dependent Kinase Inhibitor p57
- Proliferating Cell Nuclear Antigen
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Topics |
- Adrenal Hyperplasia, Congenital
(genetics, metabolism)
- Adrenal Insufficiency
- Animals
- Beckwith-Wiedemann Syndrome
(genetics, metabolism)
- Cell Line, Transformed
- Chromosomes, Human, Pair 11
- Cyclin-Dependent Kinase Inhibitor p57
(genetics, metabolism)
- Drosophila
- Exons
- Female
- Fetal Growth Retardation
(genetics, metabolism)
- Genetic Diseases, X-Linked
(genetics, metabolism)
- Genetic Loci
- Genetic Predisposition to Disease
- HEK293 Cells
- Humans
- Hypoadrenocorticism, Familial
- Male
- Mutation
- Osteochondrodysplasias
(genetics, metabolism)
- Proliferating Cell Nuclear Antigen
(genetics, metabolism)
- Protein Binding
(genetics)
- Protein Structure, Tertiary
(genetics)
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