Greig cephalopolysyndactyly syndrome 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 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 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.

     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.

The following transcription factors affect gene expression:

• Pax-6
• E2F-1
• Pax-2
• Sox9

Tissue specificity:

Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.

Molecular Function:

• Rna Polymerase Ii Regulatory Region Sequence-Specific Dna Binding
• Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Dna Binding
• Transcriptional Activator Activity, Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Binding
• Chromatin Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding
• Beta-Catenin Binding
• Histone Acetyltransferase Binding
• Histone Deacetylase Binding
• Metal Ion Binding

Biological Processes:

• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Metanephros Development
• Branching Involved In Ureteric Bud Morphogenesis
• In Utero Embryonic Development
• Positive Regulation Of Neuroblast Proliferation
• Smoothened Signaling Pathway
• Axon Guidance
• Hindgut Morphogenesis
• Heart Development
• Negative Regulation Of Cell Proliferation
• Anterior/Posterior Pattern Specification
• Proximal/Distal Pattern Formation
• Protein Processing
• Optic Nerve Morphogenesis
• Hippocampus Development
• Smoothened Signaling Pathway Involved In Ventral Spinal Cord Interneuron Specification
• Smoothened Signaling Pathway Involved In Spinal Cord Motor Neuron Cell Fate Specification
• Forebrain Dorsal/Ventral Pattern Formation
• Layer Formation In Cerebral Cortex
• Forebrain Radial Glial Cell Differentiation
• Lateral Ganglionic Eminence Cell Proliferation
• Melanocyte Differentiation
• Lung Development
• Positive Regulation Of Chondrocyte Differentiation
• T Cell Differentiation In Thymus
• Limb Morphogenesis
• Wound Healing
• Positive Regulation Of Protein Import Into Nucleus
• Odontogenesis Of Dentin-Containing Tooth
• Embryonic Digit Morphogenesis
• Negative Regulation Of Apoptotic Process
• Nose Morphogenesis
• Tongue Development
• Response To Estrogen
• Negative Thymic T Cell Selection
• Negative Regulation Of Neuron Differentiation
• Positive Regulation Of Osteoblast Differentiation
• Negative Regulation Of Smoothened Signaling Pathway
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Positive Regulation Of Alpha-Beta T Cell Differentiation
• Negative Regulation Of Alpha-Beta T Cell Differentiation
• Embryonic Digestive Tract Morphogenesis
• Embryonic Digestive Tract Development
• Developmental Growth
• Camera-Type Eye Morphogenesis
• Embryonic Skeletal System Morphogenesis
• Oligodendrocyte Differentiation
• Palate Development
• Frontal Suture Morphogenesis
• Lambdoid Suture Morphogenesis
• Sagittal Suture Morphogenesis
• Mammary Gland Specification
• Smoothened Signaling Pathway Involved In Dorsal/Ventral Neural Tube Patterning
• Artery Development
• Anterior Semicircular Canal Development
• Lateral Semicircular Canal Development
• Cell Differentiation Involved In Kidney Development
• Thymocyte Apoptotic Process
• Negative Regulation Of Canonical Wnt Signaling Pathway
• Regulation Of Bone Development