Cyclin-Dependent Kinase Inhibitor 1C (CDKN1C) is a tumor suppressor; a protein involved in the regulation of cell division. Because it is a strong, tight inhibitor of several G1 cyclin/CDK complexes, this protein is a negative regulator of cell proliferation. One of the major functions of this protein is in controlling prenatal growth, by preventing the fetus from growing abnormally large.
Mutations in CDKN1C gene cause disorders like Beckwith Wiedemann Syndromem (BWS), a condition characterized by prenatal and postnatal overgrowth. In addition, defects in CDKN1C have also been shown to result in a condition known as Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies (IMAGe). This condition is characterized by delayed prenatal and postnatal growth, and hormonal and genital abnormalities in males.
The CDKN1C gene is located on the short arm of chromosome 11 at 11p15.4, where it spans a length of about 2.5 Kb. The CDKN1C protein is made up of 316 amino acid residues and has a molecular mass of 32 kDa. The protein has three structurally distinct regions; a CDK-inhibitory domain, a Pro-Ala repeat rich domain called the PAPA region, and a c-terminal conserved QT-box motif.
The CDKN1C gene is a paternally imprinted gene. This means that the maternally inherited allele is preferentially expressed over the paternal copy. This parent specific imprinting of CDKN1C is controlled by a region of DNA nearby to the gene, called the Imprinting center 2 (IC2), which preferentially methylates the maternal copy of the CDKN1C gene.
Bastaki et al (2016) reported a case of BWS in a 9-year old Emirati boy. The patient was born to healthy, unrelated parents. He was found to have an omphalocele which contained small bowel and a small extra liver lobe. The patient was also found to suffer from cryptorchidism. Abdominal US revealed a non-progressive abdominal cyst. PCR amplification and sequencing of exons 2 and 3 of the CDKN1C gene identified a variant (c.703C>T) in the gene. According to in silico analysis results the protein change (p.Gln235X) leads to the production of a truncated protein that completely lacked the QT box. Polyphen 2 predicted that the variant was “probably damaging”. The variant was not found in either of the parents’ DNA, marking it as a de novo mutation.
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