CDKN1C mutations: two sides of the same coin

Eggermann, Thomas; Binder, Gerhard; Brioude, Frédéric; Maher, Eamonn R.; Lapunzina, Pablo; Cubellis, Maria Vittoria; Bergadá, Ignacio; Prawitt, Dirk; Begemann, Matthias

doi:10.1016/j.molmed.2014.09.001

Cited by 88 publications

(119 citation statements)

References 61 publications

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“…Later, it was shown that loss-of-function mutations in the imprinted CDKN1C gene are associated with BWS and gain-of-function mutation with SRS [for review, see Eggermann et al, 2014a]. In familial BWS cases, the occurrence of CDKN1C gene mutations is especially high, as it is found in 50-68% of the cases.…”

Section: Molecular Basis For Bwsmentioning

confidence: 99%

“…In familial BWS cases, the occurrence of CDKN1C gene mutations is especially high, as it is found in 50-68% of the cases. In 5-31% of sporadic cases, the CDKN1C point mutation is detected as the cause of BWS [Eggermann et al, 2014a;Brioude et al, 2015].…”

Section: Molecular Basis For Bwsmentioning

confidence: 99%

“…Most BWS cases are sporadic, but familial occurrence has been reported, in particular in cases of CDKN1C point mutations [Eggermann et al, 2014a], translocations involving the 11p15 region [Slavotinek et al, 1997;Smith et al, 2012], or duplication of 11p15 [Vals et al, 2015a]. In these families, BWS follows an autosomal dominant inheritance pattern with incomplete penetrance depending on the parental origin of mutation [Eggermann et al, 2014b].…”

Section: Familial Recurrence Of Srs and Bwsmentioning

confidence: 99%

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Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

Õunap

2016

Mol Syndromol

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Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS.

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Section: Molecular Basis For Bwsmentioning

confidence: 99%

Section: Molecular Basis For Bwsmentioning

confidence: 99%

Section: Familial Recurrence Of Srs and Bwsmentioning

confidence: 99%

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Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

Õunap

2016

Mol Syndromol

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“…1 Compared to the other Cip/Kip CKIs p21 cip1 and p27 kip1 , p57 kip2 exerts unique functions not compensated by the other family members, as suggested by the lethal phenotype of knockout mice 2,3 and by the developmental anomalies associated with Cdkn1c loss or misexpression in humans. 4 The unique role of the Cdkn1c protein has been ascribed both to the presence of specific biochemical features of the protein, not shared by the other family members, 5,6 and to the specific expression pattern of the gene. 7 Cdkn1c is widely expressed in most tissues during embryogenesis but its expression drastically decreases at birth, becoming restricted to a subset of tissues and organs, such as heart, brain, lung, kidney, pancreas, skeletal muscle, testis, and placenta.…”

mentioning

confidence: 99%

“…In particular, Cdkn1c defective expression is generally responsible for overgrowth disorders, such as the Beckwith-Wiedemann syndrome (BWS) and several cancer types, while Cdkn1c excessive expression is associated with growth retardation disorders, such as the Silver Russel syndrome. 4,18 Although some information has been accumulated on the regulatory strategies and molecular mechanisms involved in the Cdkn1c silencing in cancer and in the paternal allele-specific repression during imprinting, much less is known about the developmental regulation of this CKI, that is expected to affect its maternal allele.…”

mentioning

confidence: 99%

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

et al. 2016

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The cdk inhibitor p57 kip2 , encoded by the Cdkn1c gene, plays a critical role in mammalian development and in the differentiation of several tissues. Cdkn1c protein levels are carefully regulated via imprinting and other epigenetic mechanisms affecting both the promoter and distant regulatory elements, which restrict its expression to particular developmental phases or specific cell types. Inappropriate activation of these regulatory mechanisms leads to Cdkn1c silencing, causing growth disorders and cancer. We have previously reported that, in skeletal muscle cells, induction of Cdkn1c expression requires the binding of the bHLH myogenic factor MyoD to a long-distance regulatory element within the imprinting control region KvDMR1. Interestingly, MyoD binding to KvDMR1 is prevented in myogenic cell types refractory to the induction of Cdkn1c. In the present work, we took advantage of this model system to investigate the epigenetic determinants of the differential interaction of MyoD with KvDMR1. We show that treatment with the DNA demethylating agent 5-azacytidine restores the binding of MyoD to KvDMR1 in cells unresponsive to Cdkn1c induction. This, in turn, promotes the release of a repressive chromatin loop between KvDMR1 and Cdkn1c promoter and, thus, the upregulation of the gene. Analysis of the chromatin status of Cdkn1c promoter and KvDMR1 in unresponsive compared to responsive cell types showed that their differential responsiveness to the MyoD-dependent induction of the gene does not involve just their methylation status but, rather, the differential H3 lysine 9 dimethylation at KvDMR1. Finally, we report that the same histone modification also marks the KvDMR1 region of human cancer cells in which Cdkn1c is silenced. On the basis of these results, we suggest that the epigenetic status of KvDMR1 represents a critical determinant of the cell type-restricted expression of Cdkn1c and, possibly, of its aberrant silencing in some pathological conditions.

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No major contribution of IGF2 variants to the etiology of sporadic 11p15‐associated imprinting disorders

Müller

Soellner

Binder

et al. 2015

American J of Med Genetics Pt A

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CDKN1C mutations: two sides of the same coin

Cited by 88 publications

References 61 publications

Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

No major contribution of IGF2 variants to the etiology of sporadic 11p15‐associated imprinting disorders

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