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GLI3 gene

GLI family zinc finger 3
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Normal Function

The GLI3 gene belongs to a family of genes that are involved in the normal shaping (patterning) of many tissues and organs during the early stages of development before birth. To carry out this role, proteins produced from 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.

Health Conditions Related to Genetic Changes

Acrocallosal syndrome

At least two mutations in the GLI3 gene have been reported in people with features of acrocallosal syndrome, a rare condition characterized by certain brain abnormalities, extra fingers and toes (polydactyly), and distinctive facial features, including widely spaced eyes (hypertelorism) and a prominent forehead. These signs and symptoms overlap significantly with those of Greig cephalopolysyndactyly syndrome (described below), so acrocallosal syndrome resulting from GLI3 gene mutations is sometimes considered a severe form of that condition.

The GLI3 gene mutations that cause acrocallosal syndrome change single protein building blocks (amino acids) in a particular region of the GLI3 protein, which disrupts the protein's function. The malfunctioning protein likely alters the expression of certain genes during early development. The role of the GLI3 protein in brain and limb patterning may help explain why mutations lead to brain abnormalities, polydactyly, and the other features of acrocallosal syndrome.

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Greig cephalopolysyndactyly syndrome

At least 120 mutations in the GLI3 gene have been identified in people with Greig cephalopolysyndactyly syndrome, which is a rare condition characterized by polydactyly, hypertelorism, a broad forehead, and an unusually large head (macrocephaly). The genetic changes associated with Greig cephalopolysyndactyly syndrome 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. This condition can also be 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 early 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.

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Pallister-Hall syndrome

More than 40 mutations in the GLI3 gene have been found to cause Pallister-Hall syndrome, a rare condition whose major features include polydactyly, an abnormal growth in the brain called a hypothalamic hamartoma, and a malformation of the airway called a bifid epiglottis. Most of the mutations that cause Pallister-Hall syndrome occur near the middle of the gene, creating 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 repress the expression of target genes. Although this change clearly disrupts 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.

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Other disorders

Mutations in the GLI3 gene have been found in people who have polydactyly without the other features of acrocallosal syndrome, Greig cephalopolysyndactyly syndrome, or Pallister-Hall syndrome (described above). These cases are described as isolated or nonsyndromic because the polydactyly occurs without other signs and symptoms. GLI3 gene mutations can cause several forms of isolated polydactyly. These include postaxial polydactyly type A (PAP-A) and type A/B (PAP-A/B), which are characterized by an extra digit next to the little finger or the small toe. GLI3 gene mutations can also cause preaxial polydactyly type IV (PPD-IV), which is characterized by 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.

Other Names for This Gene

  • ACLS
  • GCPS
  • GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)
  • GLI3_HUMAN
  • oncogene GLI3
  • PAP-A
  • PAPA
  • PAPA1
  • PAPB
  • PHS
  • PPDIV
  • zinc finger protein GLI3

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Research Resources

References

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  • Biesecker LG, Johnston JJ. Greig Cephalopolysyndactyly Syndrome. 2001 Jul 9 [updated 2020 May 7]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1446/ Citation on PubMed
  • Biesecker LG. Pallister-Hall Syndrome. 2000 May 25 [updated 2017 May 18]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1465/ Citation on PubMed
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  • Elson E, Perveen R, Donnai D, Wall S, Black GC. De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. J Med Genet. 2002 Nov;39(11):804-6. Citation on PubMed or Free article on PubMed Central
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  • Kang S, Graham JM Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet. 1997 Mar;15(3):266-8. Citation on PubMed
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  • Radhakrishna U, Bornholdt D, Scott HS, Patel UC, Rossier C, Engel H, Bottani A, Chandal D, Blouin JL, Solanki JV, Grzeschik KH, Antonarakis SE. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet. 1999 Sep;65(3):645-55. Citation on PubMed or Free article on PubMed Central
  • Speksnijder L, Cohen-Overbeek TE, Knapen MF, Lunshof SM, Hoogeboom AJ, van den Ouwenland AM, de Coo IF, Lequin MH, Bolz HJ, Bergmann C, Biesecker LG, Willems PJ, Wessels MW. A de novo GLI3 mutation in a patient with acrocallosal syndrome. Am J Med Genet A. 2013 Jun;161A(6):1394-400. doi: 10.1002/ajmg.a.35874. Epub 2013 Apr 30. Citation on PubMed
  • Wild A, Kalff-Suske M, Vortkamp A, Bornholdt D, König R, Grzeschik KH. Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet. 1997 Oct;6(11):1979-84. Citation on PubMed
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