Trends in Molecular Medicine
ReviewCDKN1C mutations: two sides of the same coin
Section snippets
Imprinting and growth
Human height is a complex trait, with contributions from both heritable and environmental factors. Twin studies suggest that the contribution of heritability to human growth and height accounts for more than 80% of variability [1]. In addition to the strong impact of genomic DNA variation on phenotypic features such as growth, the role of epigenetic (see Glossary) mechanisms as the mediator of the reversible interactions between genes and the environment is becoming increasingly apparent 2, 3.
The chromosomal region 11p15.5
The chromosomal region 11p15.5 encodes several growth-promoting and -inhibiting factors and plays a key role in human growth and development. The region spans around 1 Mb and harbors two separate imprinting control regions (ICRs): The telomeric ICR1 (H19 DMR) is methylated on the paternal allele, whereas the centromeric ICR2 (KvDMR1; KCNQ1OT1 DMR) is maternally methylated (Figure 1). In addition to its central physiological role, it has been postulated that the 11p15.5 region is the central
CDKN1C: gene and function
The CDKN1C gene spans 1943 bp and contains four exons, two of which are protein coding (Figure 2). The CDKN1C protein includes three functional domains: (i) the N-terminal CDK inhibition domain (CdK); (ii) the proline–alanine repeat (PAPA) domain, which includes a hexanucleotide repeat encoding a proline–alanine stretch that is variable in length; and (iii) the C-terminal proliferating cell nuclear antigen (PCNA)-binding domain. CDKN1C negatively regulates cell proliferation by inhibiting
Congenital disorders associated with CDKN1C mutations
Due to its function as a negative regulator of cellular proliferation, alterations in CDKN1C should be associated with aberrant growth. Indeed, mutations of CDKN1C contribute to the mutational spectrum of BWS [38]. These CDKN1C mutations belong to a spectrum of genomic and epigenetic disturbances within the chromosomal region 11p15.5 that cause BWS 38, 39, 40. Interestingly, the opposite statuses of these 11p15.5 alterations are detectable in SRS, a primordial growth-retardation disorder (Box 1
Mutations of CDKN1C: types and functional relevance
The nature of molecular alterations affecting the sequence and copy number of CDKN1C and its neighboring genomic region show an impressive correlation with the phenotype of their carriers and allow major insights into the function and role of this cell cycle-inhibiting protein. In general, three types of mutation can be distinguished: (i) loss-of-function CDKN1C point mutations that are associated with BWS; (ii) gain-of-function CDKN1C point mutations that cause growth-retardation syndromes
Relevance for genetic counseling and clinical management
Mutations within the CDKN1C coding sequence can lead to opposite phenotypes and this association appears to be very strict; therefore, the phenotype in families with CDKN1C point mutations should be uniform: either growth retardation/SRS or BWS should occur in the same family. However, only maternal inheritance of the CDKN1C variant is associated with an aberrant phenotype (Figure 3A). Due to the silencing of the paternal CDKN1C copy, males carrying a CDKN1C mutation are not at risk of having
Concluding remarks
Loss-of-function mutations of the CDKN1C gene have been known to cause overgrowth, but with recent reports of gain-of-function mutations in CDKN1C in growth-retarded patients the last gap in the impressive strictly opposite molecular spectrum of molecular alterations in 11p15.5 in growth-retardation and overgrowth syndromes could be closed. Based on the current data, we suggest that testing of CDKN1C should be offered to patients with BWS or IMAGe syndrome, whereas the clinical diagnosis of SRS
Acknowledgments
T.E., D.P., and M.B. are supported by the Bundesministerium für Bildung und Forschung (Network ‘Imprinting Diseases’ 01GM1114C to T.E. and 01GM114D to D.P.) and Ipsen Pharma. The authors are members of COST Action BM1208 and the European Congenital Imprinting Disorders Network (EUCID.net) (http://www.imprinting-disorders.eu).
Glossary
- Differentially methylated region (DMR)
- a genomic region with different methylation statuses in different tissues, resulting in differential epigenetic regulation of gene expression.
- Deletion
- an aberration in which part of a chromosome or a DNA sequence is missing.
- DNA methylation
- a molecular modification where a methyl group is added to cytosine residues.
- Duplication
- an aberration in which part of a chromosome or a DNA sequence is duplicated.
- Epigenetics
- DNA modifications like methylation or histone
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2021, Molecular and Cellular EndocrinologyCitation Excerpt :IMAGe mutations typically cause restricted growth (Arboleda et al., 2012). Thus variants in the same gene cause both the IMAGe adrenal hypoplasia syndrome with IUGR and the Beckwith-Wiedemann adrenal hyperplasia overgrowth syndrome (Eggermann et al., 2014). Interestingly, biallelic mutations in POLE1 also cause IMAGe syndrome (Logan et al., 2018).