| Full gene name: | cyclin-dependent kinase inhibitor 1C (p57, Kip2) |
|---|---|
| Entrez Gene ID: | 1028 |
| Location: | 11p15.5 |
| Synonyms: | BWS, WBS, BWCR, IMAGE, KIP2, p57 |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs2237892 | 64697 | downstream |
| rs231362 | 212977 | downstream |
This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
| OMIM ID: | `OMIM ID 600856 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 BECKWITH-WIEDEMANN SYNDROME
Hatada et al. (1996) identified a heterozygous glu47-to-ter mutation in a 7-year-old boy with BWS (130650) caused by a C-to-T transition at nucleotide 399. They noted that this mutation would lead to a severely truncated polypeptide of 46 residues with disruption of the Cdk inhibitory domain and loss of the QT domain and the proline/alanine repeats. This mutation disrupts a PstI restriction site; digestion of the PCR-amplified DNA with PstI led to the identification of a novel 219-bp fragment in the patient in addition to 3 other fragments which were also detected in normal individuals. The parents, grandparents, and sister of the patient were healthy. PCR-amplified DNA from the parents was examined, and the mother was found to have the same 219-bp fragment that was present in the mutant allele of the patient. The father of the patient had only the normal allele. Hatada et al. (1996) reported that the mother inherited the abnormal allele from her father. She was phenotypically normal, since p57(KIP2) is expressed from the maternal allele.
By functional analysis of the glu47-to-ter mutation in the patient reported by Hatada et al. (1996), Bhuiyan et al. (1999) found that the mutation, which occurs in the Cdk inhibitory domain, renders the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization.
.0002 BECKWITH-WIEDEMANN SYNDROME
Hatada et al. (1996) described a p57(KIP2) mutation in a 3-month-old girl with BWS (130650). This patient was heterozygous for a T-to-AG mutation at nucleotide 1086 that modified the 9 amino acids downstream, resulting in premature translation termination. The resultant 284-amino acid truncated polypeptide lacks the QT domain. The mutation disrupts an MboII restriction site in the gene.
By functional analysis of this mutation in the patient reported by Hatada et al. (1996), Bhuiyan et al. (1999) found that the mutant protein, although completely retaining its cell cycle regulatory activity, lacks nuclear localization, and is thus prevented from performing its role as an active cell cycle inhibitor. The mutant allele was inherited from the mother, as was the case with the glu47-to-ter mutation (600856.0001) described by Hatada et al. (1996).
.0003 BECKWITH-WIEDEMANN SYNDROME
In a familial case of BWS (130650), Hatada et al. (1997) found a heterozygous CT-to-G transversion/deletion at nucleotide 570 of CDKN1C, leading to a frameshift at codon 104 resulting in the loss of the QT domain and the PAPA repeats of the gene product. The patient’s father was normal but his mother had gigantism during infancy. The patient’s sister also had BWS and showed the same mutation.
.0004 BECKWITH-WIEDEMANN SYNDROME
In a patient with BWS (130650), Hatada et al. (1997) found heterozygosity for a C-to-A transversion at nucleotide 1000 of the CDKN1C gene, changing ser247 (TCG) to a termination (TAG) codon. This resulted in a truncated polypeptide of 246 residues with a disruption of the QT domain. The mutation pointed to an important role of the QT domain in growth regulation.
.0005 BECKWITH-WIEDEMANN SYNDROME
In a 32-year-old man with BWS (130650), Romanelli et al. (2010) identified a heterozygous 845C-G transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Other features included cryptorchidism and hypoglycemia. The mutation resulted in the same amino acid change as that found in another patient (845C-A; 600856.0006), suggesting a possible hotspot at this nucleotide.
.0006 BECKWITH-WIEDEMANN SYNDROME
In a 7-year-old boy with BWS (130650), Romanelli et al. (2010) identified a heterozygous 845C-A transversion in the CDKN1C gene, resulting in a ser282-to-ter (S282X) substitution in domain III. He had generalized overgrowth, macroglossia, ear creases, and omphalocele. Additional features included cleft palate and an extra nipple. The mutation resulted in the same amino acid change as that found in another patient (845C-G; 600856.0005), suggesting a possible hotspot at this nucleotide.
.0007 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
In 7 affected members of a 5-generation Argentinian family with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), originally reported by Bergada et al. (2005), Arboleda et al. (2012) identified heterozygosity for an 825T-G transversion in the CDKN1C gene, resulting in a phe276-to-val (F276V) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in dbSNP129. Inheritance of IMAGE syndrome was only through maternal transmission of the F276V mutation: sequencing in 24 family members confirmed that only individuals who inherited the 825T-G mutation on the maternal allele were affected, presumably due to epigenetic silencing of the mutated allele when it occurred on the paternal allele. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the F276V mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect.
.0008 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 826T-C transition in the CDKN1C gene, resulting in a phe276-to-ser (F276S) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in dbSNP129.
.0009 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 835G-C transversion in the CDKN1C gene, resulting in an arg279-to-pro (R279P) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in dbSNP129.
.0010 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 819G-A transition in the CDKN1C gene, resulting in an asp274-to-asn (D274N) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in dbSNP129.
.0011 INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES
In a patient with intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (IMAGE syndrome; 614732), Arboleda et al. (2012) identified heterozygosity for an 831A-G transition in the CDKN1C gene, resulting in a lys278-to-glu (K278E) substitution at a highly conserved residue near the PCNA (176740)-binding domain. The variant was not present in dbSNP129. Analysis of transfected HEK293 cells suggested disruption of PCNA binding. Overexpression of the K278E mutant in Drosophila resulted in moderate restriction of wing and eye growth, suggestive of a gain-of-function effect.
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