GLIS Family Zinc Finger Protein 3

Alternative Names

  • GLIS3
  • GLI-Similar Protein 3
  • Zinc Finger Protein 515
  • ZNF515
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OMIM Number

610192

Gene Map Locus
9p24.2

Description

GLIS3 encodes a transcription factor belonging to the Kruppel-like zinc finger protein family.  The GLIS3 nuclear protein has five C2H2-type zinc finger domains and functions as both an activator and repressor of transcription, thus playing a key regulatory role in development.  GLIS3 is expressed in several tissues of the body but is most highly expressed in islet beta cells.  It is found to be associated with pancreatic endocrine development, beta-cell maintenance and insulin regulation.

GLIS3 expression occurs early in embryogenesis and thus it is easy to see how defects in the gene can have severe pathological consequences.  Mutations in the GLIS3 gene are associated with NDH syndrome, a congenital disorder characterized by intrauterine growth retardation, non-immune neonatal diabetes mellitus, congenital hypothyroidism and facial dysmorphism.  Genome wide association studies have also identified GLIS3 as a risk locus for Type-1 and Type-2 Diabetes.

Molecular Genetics

GLIS3 is located on the short arm of chromosome 9.  It is made up of 19 exons and is around 524 Kb in size.  It encodes a protein product that is 83 kDa in size and is made of 775 amino acids.  Several alternatively spliced transcripts of GLIS3 exist.  These transcripts are tissue-specific and vary in expression levels.  The major transcript, 7.5 kb in size, is found to be highly expressed in the pancreas and thyroid.

Several mutations in the GLIS3 gene have been associated with NDH syndrome.  The most common of these mutations are partial gene deletions resulting in the absence of tissue-specific transcripts of the gene.  Other mutations include homozygous insertions that result in a frameshift and a truncated protein or transversions that result in amino acid substitutions at highly conserved residues of the protein.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Senee et al. (2006) reported on individuals belonging to two consanguineous families from Saudi Arabia that were affected by neonatal diabetes, congenital hypothyroidism and facial anomalies.  A genome wide linkage scan mapped the syndrome to chromosome 9p in these families. Using PCR assays, a homozygous 426 kb deletion in the affected individual from one of the families was discovered.  This deletion was found to affect the GLIS3 gene.  In the other family, a homozygous insertion 2067insC was discovered in the GLIS3 gene and found to result in a frameshift and a truncated protein.  Based on mouse studies, this was predicted to result in a non-functional protein.  GLIS3 RNA expression levels in the blood of affected individuals from the family with the insertion mutation were found to be extremely reduced.  The gene structure and the expression of GLIS3 in various tissues were studied.  The study found several different tissue-specific transcripts of the gene with varied size and expression levels.  A major 7.5kb transcript, expressed in the pancreas and thyroid, was found to be affected by the deletion mutation.  A retina specific transcript starting in exon 12 was discovered and found to be affected by the deletion.  As the patient in this family had congenital glaucoma, the retina-specific transcript was predicted to play a key role in eye development.  Thus the variability in phenotype between the families was explained by the presence of defective GLIS3 protein in the case of the insertion mutation, and by the presence of multiple transcripts in the case of the deletion mutation. They study also found that GLIS3 is expressed in the pancreas from early developmental stages and is associated in the development of pancreatic beta cells.

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