The GLI3 gene provides instructions for creating a protein important for early development. As a transcription factor, it attaches to DNA to control the activity of other genes, shaping tissues and organs as an embryo grows. It is part of the Sonic Hedgehog pathway, a signaling system that directs cell growth, specialization, and the formation of many body structures.
GLI3’s Functions in Embryonic Development
The GLI3 protein has a dual role in regulating gene expression. Within the Sonic Hedgehog (Shh) signaling pathway, it can function as an activator that turns genes on or a repressor that turns them off. The full-length protein, GLI3A, is an activator, while a shorter, processed form, GLI3R, is a repressor. The balance between these activator and repressor forms dictates the proper formation of structures.
This function is evident in limb development, where the balance of GLI3A and GLI3R determines the number and identity of fingers and toes. The gene helps establish the anterior-posterior axis, which is the thumb-to-pinky layout of the hand, ensuring the correct number of digits form in the correct places. Beyond the limbs, GLI3 is involved in developing the head and face, influencing features like the distance between the eyes and the size of the forehead. The protein’s role also extends to brain development, where it participates in patterning the forebrain.
When GLI3 Goes Awry: Associated Genetic Syndromes
Mutations in the GLI3 gene disrupt its function and can lead to several genetic syndromes, with the type and severity relating to the specific change within the gene. One of the primary conditions is Greig cephalopolysyndactyly syndrome (GCPS). Individuals with GCPS present with extra fingers or toes (polydactyly), webbing of digits (syndactyly), widely spaced eyes (hypertelorism), and a large head (macrocephaly).
Another condition is Pallister-Hall syndrome (PHS), characterized by polydactyly, often involving a central extra digit, and a noncancerous brain tumor called a hypothalamic hamartoma. Other features can include a split in the epiglottis and an obstructed anal opening.
Less commonly, mutations can cause Acrocallosal syndrome (ACLS) or result in isolated polydactyly, where an individual has extra digits without the other signs of a broader syndrome. The features of these conditions can vary significantly, even among members of the same family.
How GLI3 Alterations Cause Developmental Differences
The outcomes in GLI3-related syndromes are linked to how mutations affect the protein’s function. The two primary mechanisms are haploinsufficiency and the creation of a truncated, overactive repressor protein.
Greig cephalopolysyndactyly syndrome (GCPS) is caused by haploinsufficiency. This occurs when a mutation inactivates one of the two copies of the GLI3 gene, resulting in only half the normal amount of GLI3 protein. This reduction disturbs the balance between the activator and repressor forms, impairing genetic signaling.
Pallister-Hall syndrome (PHS) results from mutations in the middle of the GLI3 gene that produce an abnormally short protein. This truncated protein acts as a constant repressor, turning off target genes and overriding normal regulatory signals. This overactive repressor function leads to the specific features of PHS, such as hypothalamic hamartomas.
The location of the mutation determines the consequence. Mutations that eliminate the protein’s ability to bind to DNA cause a loss of function and GCPS. In contrast, mutations that preserve the DNA-binding portion but remove the activator end create the overactive repressor associated with PHS.
Identifying and Living with GLI3-Related Conditions
Diagnosis of a GLI3-related condition begins with a clinical evaluation. For instance, a combination of polydactyly and widely spaced eyes may suggest GCPS, while a hypothalamic hamartoma with polydactyly points to PHS. A definitive diagnosis requires molecular genetic testing to identify a mutation in the GLI3 gene.
Management focuses on specific symptoms and requires a multidisciplinary healthcare team. Surgical intervention is common for limb differences, such as removing extra digits or separating fused digits to improve function.
Individuals with these conditions may require ongoing surveillance. For those with PHS, monitoring for pituitary gland dysfunction and managing potential seizures is important. Developmental therapies, educational support, and genetic counseling are also offered to individuals and their families.