Domain Specific-mutation in CDKN1C is theCause of Image Syndrome

ARBOLEDA, VALERIE; BRASLAVSKY, DÉBORA; LEE, HANE; PARNAIK, RAHUL; FLEMING, ALICE; BANERJEE, ABHIK; FERRAZ-DE-SOUZA, BRUNO; DÉLOT, EMMANUÈLE; RODRIGUEZ-FERNANDEZ, IMILCE; DELL’ANGELICA, ESTEBAN; NELSON, STANLEY; MARTINEZ-AGOSTO JULIAN; ACHERMANN, JOHN; BERGADÁ, IGNACIO; VILAIN, ERIC

Montevideo

Congreso; XXIII Annual Meeting of the Paediatrics Endocrinology Latinoamerican Society; 2012

XXIII Annual Meeting of the Paediatrics Endocrinology Latinoamerican Society

IMAGe Syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) OMIM 300290, is an undergrowth developmental disorder with life-threatening consequences. Identity-by-descent analysis in an Argentinean family with IMAGe syndrome identified a 17.2Mb locus on 11p15 that segregated in affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validated by dideoxysequencing, identified c.825T>G mutation resulting in a p.Phe276Val missense alteration in CDKN1C (P57KIP2). Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression and targeted expression of IMAGe-associated CDKN1C mutation in Drosophila caused severe eye growth defects, suggesting a gain-offunction mechanism. Furthermore, IMAGe- associated mutation clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding. In contrast loss-of-function mutations in the N-terminal cyclin dependent kinase domain of CDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism forCDKN1C (P57KIP2). Familial analysis demonstrated an imprinted mode of inheritance where only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression and targeted expression of IMAGe-associated CDKN1C mutation in Drosophila caused severe eye growth defects, suggesting a gain-offunction mechanism. Furthermore, IMAGe- associated mutation clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding. In contrast loss-of-function mutations in the N-terminal cyclin dependent kinase domain of CDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism forCDKN1C inhibits cell-cycle progression and targeted expression of IMAGe-associated CDKN1C mutation in Drosophila caused severe eye growth defects, suggesting a gain-offunction mechanism. Furthermore, IMAGe- associated mutation clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding. In contrast loss-of-function mutations in the N-terminal cyclin dependent kinase domain of CDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism forCDKN1C mutation in Drosophila caused severe eye growth defects, suggesting a gain-offunction mechanism. Furthermore, IMAGe- associated mutation clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding. In contrast loss-of-function mutations in the N-terminal cyclin dependent kinase domain of CDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism forCDKN1C and resulted in loss of PCNA binding. In contrast loss-of-function mutations in the N-terminal cyclin dependent kinase domain of CDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism forCDKN1C has been shown to result in an opposite syndrome, Beckwith-Wiedemann Syndrome, an overgrowth syndrome with adrenalomegaly. This novel mechanism for CDKN1C regulation revealed the undergrowth-associated IMAGe syndrome and may in the future elucidate previously unidentified mechanisms involved in cell transformation and cell cycle progression.regulation revealed the undergrowth-associated IMAGe syndrome and may in the future elucidate previously unidentified mechanisms involved in cell transformation and cell cycle progression.