The GZF1 gene encodes a transcriptional repressor. This protein binds to target DNA at a 12-bp long sequence known as the GZF1 responsive element (GRE) and suppresses expression in a dose-dependent manner. It is believed that the HOX10 gene, which encodes a retina-specific homeobox, contains a GRE and is downregulated by GZF1.
While the gene is yet to be fully characterized, studies of the mouse ortholog gene have helped better understand the function of GZF1. Immunofluorescence analysis has shown the expression of mouse Gzf1 in the eyes and limbs of developing mice. Knockdown studies have also implicated the mouse ortholog in the branching involved in uteric bud morphogenesis.
The gene is located on the short arm of chromosome 20 and spans a length of 11.4 kb of DNA. Its coding sequence is contained within 9 exons and it encodes an 80.4 kDa protein product consisting of 711 amino acids. Alternative splicing results in an additional isoform of the GZF1 protein containing just 220 amino acids. GZF1 contains an N-terminal BTB (broad complex, Tramtrack, Bric a brac)-POZ (poxvirus and zinc finger) domain and ten C2H2 zinc-finger domains. The gene is seen to be expressed in the brain, heart, skeletal muscle, kidney and liver.
Patel et al. (2017) described two consanguineous Saudi families with a Larsen syndrome phenotype. 2 siblings in family 1, a 16-year-old girl and a 2.5-year-old boy, suffered from severe myopia, hips and knees dislocation, talipes and short stature. Family 2 consisted of three brothers (ages 20, 16 and 7 years) exhibiting hyper-extensibility of large joints, severe myopia and short stature. Combined autozygome and exome analysis helped identify the GZF1 mutation c.865G>T (pGlu289*) in patients from family 1 and the GZF1 mutation c.1054dup (p.Thr352Asnfs*50) in patients from family 2. Both homozygous truncating mutations fully segregated with the phenotype and were predicted to eliminate C2H2 zinc-finger domains, required for DNA binding. They were also absent from 2379 Saudi exomes and the ExAC browser. Further, by conducting a global transcriptional profiling of cells from affected individuals, the authors revealed a pattern of gene dysregulation. Several matrix remodeling genes were found to be significantly dysregulated, including P3H2, a gene implicated in a Mendelian form of severe myopia. Based on these findings, it was suggested that GZF1 mutations cause Larsen syndrome with myopia and articular involvement.
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