CDKN1C

The CDKN1C gene provides instructions for making a protein that helps regulate growth. This protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It also is involved in controlling growth before birth, preventing the developing fetus from becoming too large.

People generally inherit one copy of a gene from their mother and one copy from their father. For most genes, both copies are fully turned on (active) in cells. The CDKN1C gene, however, is most active when it is inherited from a person's mother. The copy of CDKN1C inherited from a person's father is active at much lower levels in most tissues. This sort of parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting. When genomic imprinting reduces the activity of the copy of a gene inherited from the father, that gene is said to be paternally imprinted.

CDKN1C is part of a cluster of genes on the short (p) arm of chromosome 11 that undergo genomic imprinting. A nearby region of DNA known as imprinting center 2 (ICR2) or KvDMR controls the parent-specific genomic imprinting of CDKN1C and several other genes thought to help regulate growth.

Beckwith-Wiedemann syndrome - caused by mutations in the CDKN1C gene

Beckwith-Wiedemann syndrome is a condition that causes overgrowth, increases the risk of tumors, and has other signs and symptoms that affect many parts of the body. At least half of all cases of Beckwith-Wiedemann syndrome result from changes in a process called methylation that affects the ICR2 region. In genes that undergo genomic imprinting, the parent of origin is often marked, or "stamped," on the gene during the formation of an egg or sperm cell. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. The ICR2 region is normally methylated on the maternally inherited copy of chromosome 11.

In many people with Beckwith-Wiedemann syndrome, the ICR2 region has too few methyl groups attached (hypomethylation). This abnormality disrupts the regulation of several genes that are normally controlled by ICR2. Specifically, hypomethylation of the ICR2 region greatly reduces the activity of the CDKN1C gene. Because this gene normally restrains growth, a loss of its activity leads to the features of Beckwith-Wiedemann syndrome, including overgrowth and an increased risk of tumors.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the ICR2 region. Like abnormal methylation, these deletions disrupt the activity of several genes, including CDKN1C.

Beckwith-Wiedemann syndrome can also result from mutations within the CDKN1C gene itself. Because this gene is paternally imprinted, Beckwith-Wiedemann syndrome results when the mutation is present on the maternally inherited copy of the gene. More than two dozen such mutations have been identified. Some of these genetic changes lead to an abnormally short, nonfunctional version of the CDKN1C protein, while others alter single protein building blocks (amino acids) or delete a small number of amino acids from the protein. All of these mutations are described as "loss-of-function" because they alter the structure of the CDKN1C protein such that it can no longer control cell growth and division effectively. The resulting problems with growth regulation lead to overgrowth and the other features of Beckwith-Wiedemann syndrome.

intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies - caused by mutations in the CDKN1C gene

Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, commonly known by the acronym IMAGe, is a rare syndrome that affects the growth of many parts of the body. At least five mutations in the CDKN1C gene have been found to cause this condition. Because this gene is paternally imprinted, IMAGe syndrome results only when the mutation is present on the maternally inherited copy of the gene.

The CDKN1C gene mutations that cause IMAGe syndrome replace single amino acids in a region known as the proliferating cell nuclear antigen (PCNA)-binding domain near the end of the gene. Researchers believe that these genetic changes alter the structure and function of the CDKN1C protein in a way that impairs normal growth starting before birth. Because these mutations are thought to enhance the gene's usual function of restraining excess growth, they are described as "gain-of-function." However, it is unclear how the mutations lead to the specific features of IMAGe syndrome.