CDKN1C mutations: two sides of the same coin

•Opposed functional mutations in CDKN1C cause opposite clinical features. •Loss-of-function mutations cause overgrowth. •Gain-of-function mutations in the PCNA domain result in growth restriction. •Only maternally inherited mutations in CDKN1C are associated with disturbed growth. Cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) negatively regulates cellular proliferation and it has been shown that loss-of-function mutations in the imprinted CDKN1C gene (11p15.5) are associated with the overgrowth disorder Beckwith–Wiedemann syndrome (BWS). With recent reports of gain-of-function mutations of the PCNA domain of CDKN1C in growth-retarded patients with IMAGe syndrome or Silver–Russell syndrome (SRS), its key role for growth has been confirmed. Thereby, the last gap in the spectrum of molecular alterations in 11p15.5 in growth-retardation and overgrowth syndromes could be closed. Recent functional studies explain the strict association of CDKN1C mutations with clinically opposite phenotypes and thereby contribute to our understanding of the function and regulation of the gene in particular and epigenetic regulation in general. Cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) negatively regulates cellular proliferation and it has been shown that loss-of-function mutations in the imprinted CDKN1C gene (11p15.5) are associated with the overgrowth disorder Beckwith–Wiedemann syndrome (BWS). With recent reports of gain-of-function mutations of the PCNA domain of CDKN1C in growth-retarded patients with IMAGe syndrome or Silver–Russell syndrome (SRS), its key role for growth has been confirmed. Thereby, the last gap in the spectrum of molecular alterations in 11p15.5 in growth-retardation and overgrowth syndromes could be closed. Recent functional studies explain the strict association of CDKN1C mutations with clinically opposite phenotypes and thereby contribute to our understanding of the function and regulation of the gene in particular and epigenetic regulation in general. a genomic region with different methylation statuses in different tissues, resulting in differential epigenetic regulation of gene expression. an aberration in which part of a chromosome or a DNA sequence is missing. a molecular modification where a methyl group is added to cytosine residues. an aberration in which part of a chromosome or a DNA sequence is duplicated. DNA modifications like methylation or histone modification that do not change the DNA sequence and often affect gene expression. aberrant silencing/activation of gene expression without a change in the DNA sequence but due to an epigenetic change (e.g., by aberrant DNA methylation). a chromosomal region that regulates the expression or silencing of imprinted genes. a group of currently eight congenital disorders caused by molecular alterations of imprinted genes (or chromosomal regions). genes that are expressed in a parent-of-origin-specific manner. digital analysis of data obtained from the analysis of short DNA sequences from loci all over the genome. It detects genomic copy number variations at a higher resolution than conventional karyotyping. states that the inequality of imprinting patterns between parental genomes is a result of the differing interests of the parents. abnormalities caused by the rearrangement of parts of one or more chromosomes. the unique inheritance of both chromosomes of a pair from only one parent rather than from both parents.