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

Donatella Milani, Lidia Pezzani, Silvia Tabano, Monica Miozzo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)169-175
Number of pages7
JournalApplication of Clinical Genetics
Volume7
DOIs
Publication statusPublished - Sep 16 2014

Fingerprint

Mutation
Genes
Growth
Phenotype
Alleles
Genomic Imprinting
Cyclins
Protein Stability
Proliferating Cell Nuclear Antigen
Nuclear Proteins
Epigenomics
Maintenance
Mothers
Cell Proliferation
Proteins

Keywords

  • Beckwith–Wiedemann syndrome
  • CDKN1C
  • Genomic imprinting
  • Growth disturbances
  • IMAGe syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Beckwith–Wiedemann and IMAGe syndromes : Two very different diseases caused by mutations on the same gene. / Milani, Donatella; Pezzani, Lidia; Tabano, Silvia; Miozzo, Monica.

In: Application of Clinical Genetics, Vol. 7, 16.09.2014, p. 169-175.

Research output: Contribution to journalArticle

@article{c85ea890de884a5c90c481e5f65ef730,
title = "Beckwith–Wiedemann and IMAGe syndromes: Two very different diseases caused by mutations on the same gene",
abstract = "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.",
keywords = "Beckwith–Wiedemann syndrome, CDKN1C, Genomic imprinting, Growth disturbances, IMAGe syndrome",
author = "Donatella Milani and Lidia Pezzani and Silvia Tabano and Monica Miozzo",
year = "2014",
month = "9",
day = "16",
doi = "10.2147/TACG.S35474",
language = "English",
volume = "7",
pages = "169--175",
journal = "Application of Clinical Genetics",
issn = "1178-704X",
publisher = "Dove Medical Press Ltd.",

}

TY - JOUR

T1 - Beckwith–Wiedemann and IMAGe syndromes

T2 - Two very different diseases caused by mutations on the same gene

AU - Milani, Donatella

AU - Pezzani, Lidia

AU - Tabano, Silvia

AU - Miozzo, Monica

PY - 2014/9/16

Y1 - 2014/9/16

N2 - 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.

AB - 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.

KW - Beckwith–Wiedemann syndrome

KW - CDKN1C

KW - Genomic imprinting

KW - Growth disturbances

KW - IMAGe syndrome

UR - http://www.scopus.com/inward/record.url?scp=84907519365&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907519365&partnerID=8YFLogxK

U2 - 10.2147/TACG.S35474

DO - 10.2147/TACG.S35474

M3 - Article

AN - SCOPUS:84907519365

VL - 7

SP - 169

EP - 175

JO - Application of Clinical Genetics

JF - Application of Clinical Genetics

SN - 1178-704X

ER -