Beckwith-Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene

Genomic imprinting is an epigenetically regulated mechanism leading to parental-origin allele-specific expression. Beckwith-Wiedemann syndrome (BWS) is an imprinting disease related to 11p15.5 genetic and epigenetic alterations, among them loss-of-function CDKN1C mutations. Intriguing is that CDKN1C gain-of-function variations were recently found in patients with IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies). BWS and IMAGe share an imprinted mode of inheritance; familial analysis demonstrated the presence of the phenotype exclusively when the mutant CDKN1C allele is inherited from the mother. Interestingly, both IMAGe and BWS are characterized by growth disturbances, although with opposite clinical phenotypes; IMAGe patients display growth restriction whereas BWS patients display overgrowth. CDKN1C codifies for CDKN1C/KIP2, a nuclear protein and potent tight-binding inhibitor of several cyclin/Cdk complexes, playing a role in maintenance of the nonproliferative state of cells. The mirror phenotype of BWS and IMAGe can be, at least in part, explained by the effect of mutations on protein functions. All the IMAGe-associated mutations are clustered in the proliferating cell nuclear antigen-binding domain of CDKN1C and cause a dramatic increase in the stability of the protein, which probably results in a functional gain of growth inhibition properties. In contrast, BWS mutations are not clustered within a single domain, are loss-of-function, and promote cell proliferation. CDKN1C is an example of allelic heterogeneity associated with opposite syndromes.