GLI3

The GLI3 gene belongs to a family of genes that are involved in the normal shaping (patterning) of many tissues and organs during embryonic development. To carry out this role, proteins made by genes in the GLI family attach to specific regions of DNA and help control whether particular genes are turned on or off (gene expression). GLI proteins are called transcription factors on the basis of this action.

Proteins in the GLI family function in the same molecular pathway as a protein called Sonic Hedgehog. This pathway is essential for early development. It plays a role in cell growth, cell specialization, and the patterning of structures such as the brain and limbs. Depending on signals from Sonic Hedgehog, the GLI3 protein can either turn on (activate) or turn off (repress) other genes. Researchers are working to identify the genes targeted by the GLI3 protein during development.

Greig cephalopolysyndactyly syndrome - caused by mutations in the GLI3 gene

Several types of mutations in the GLI3 gene have been identified in people with Greig cephalopolysyndactyly syndrome. These genetic changes include insertions or deletions of a small amount of DNA and changes in single DNA building blocks (base pairs) in critical regions of the gene. In other cases, this condition is caused by chromosomal abnormalities involving the region of chromosome 7 that contains the GLI3 gene. The genetic changes that cause Greig cephalopolysyndactyly syndrome prevent one copy of the gene in each cell from producing any functional GLI3 protein. As a result, only half the normal amount of this protein is available to control the expression of target genes during embryonic development. It remains unclear how a reduced amount of the GLI3 protein disrupts development of the limbs, head, and face and causes the specific features of Greig cephalopolysyndactyly syndrome.

Pallister-Hall syndrome - caused by mutations in the GLI3 gene

Most of the mutations responsible for Pallister-Hall syndrome occur near the middle of the GLI3 gene. These genetic changes typically create a premature stop signal in the instructions for making the GLI3 protein. As a result, cells produce an unusually short version of the protein. Unlike the full-length GLI3 protein, which can turn target genes on or off, the short protein can only turn off (repress) the expression of target genes. Although this defect clearly disrupts aspects of embryonic development, it is not known how the altered function of the GLI3 protein leads to the varied signs and symptoms of Pallister-Hall syndrome.

other disorders - caused by mutations in the GLI3 gene

Mutations in the GLI3 gene have been found in people with several forms of polydactyly (the presence of extra fingers and/or toes). These cases are described as isolated or nonsyndromic because the polydactyly occurs without other signs and symptoms, such as brain abnormalities or widely spaced eyes. GLI3 mutations can cause two types of polydactyly that are characterized by an extra digit next to the little finger or the small toe. These conditions are called postaxial polydactyly type A (PAP-A) and type A/B (PAP-A/B). Another form of polydactyly, preaxial polydactyly type IV (PPD-IV), can also result from mutations in the GLI3 gene. People with this condition have extra digits next to the thumb or big toe (hallux) and fused skin between some fingers and toes (cutaneous syndactyly). PPD-IV also can include extra digits in other positions on the hands or feet. The pattern of polydactyly seen with PPD-IV is similar to that of Greig cephalopolysyndactyly syndrome, and some researchers suggest that PPD-IV may be a very mild form of that syndrome.