HGNC Approved Gene Symbol: GFI1B
Cytogenetic location: 9q34.13 Genomic coordinates (GRCh38) : 9:132,945,531-132,993,434 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.13 | Bleeding disorder, platelet-type, 17 | 187900 | Autosomal dominant; Autosomal recessive | 3 |
The GFI1B gene encodes a transcriptional repressor important for hematopoiesis and megakaryopoiesis (summary by Monteferrario et al., 2014).
Tong et al. (1998) isolated a full-length cDNA clone of a novel gene, which they designated Gfi1b, from a murine spleen cDNA library. They found that Gfi1b encodes a 330-amino acid zinc finger protein with a SNAG repressor domain. Gfi1b is 97% identical in the zinc finger domain and 95% identical in the SNAG domain to Gfi1 (600871). Northern blot analysis showed that Gfi1b is expressed in bone marrow and spleen but not in kidney, liver, lung, heart, or brain. In contrast, Gfi1 is expressed primarily in bone marrow and thymus.
Rodel et al. (1998) screened a cDNA library from human umbilical cord mononuclear cells with a conserved sequence from chicken Gfi and used PCR to generate a 1.1-kb cDNA fragment of GFI1B. Northern blot analysis showed that human GFI1B expression was highest in bone marrow and fetal liver as well as in the chronic myeloid leukemia cell line K562. It was expressed at lower levels in other hematopoietic precursor cells.
Tong et al. (1998) found that Gfi1b was downregulated in myelomonocytic M1 cells in the presence of interleukin-6 (IL6; 147620). However, forced expression of Gfi1b inhibited IL6-induced cell cycle arrest and differentiation and inhibited expression of the p21(WAF1) (CDKN1A; 116899) promoter. The inhibition was attributed to a transcriptional repressor contained in the Gfi1b SNAG domain.
By coimmunoprecipitation assays with mouse and human cells, Saleque et al. (2007) showed that LSD1 (AOF2; 609132), COREST (RCOR; 607675), HDAC1 (601241), and HDAC2 (605164) interacted with both GFI1 and GFI1B in endogenous complexes. The N-terminal SNAG repression domain of GFI1 and GFI1B was required for their association with COREST and LSD1. Mouse Gfi1b recruited these cofactors to the majority of target gene promoters in vivo. Inhibition of Corest and Lsd1 perturbed differentiation of mouse erythroid, megakaryocytic, and granulocytic cells, as well as primary erythroid progenitors. Lsd1 depletion derepressed GFI targets in lineage-specific patterns, accompanied by enhanced histone-3 (see 602810) lys4 methylation at the respective promoters. Saleque et al. (2007) concluded that GFI complexes catalyze serial histone modification of their targets, leading to their graded silencing.
Northcott et al. (2014) described a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4 of childhood medulloblastoma (see 155255), resulting in specific and mutually exclusive activation of the growth factor-independent-1 family protooncogenes GFI1 (600871) and GFI1B. Somatic structural variants juxtapose coding sequences from either of these genes proximal to active enhancer elements, including superenhancers, instigating oncogenic activity. Northcott et al. (2014) concluded that their results, supported by evidence from mouse models, identified GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicated 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
Rodel et al. (1998) determined that the coding region of human GFI1B is spread over 5 kb and contains 6 coding exons.
By sequence comparison within a mapped cosmid (GenBank AC000393), Rodel et al. (1998) mapped the human GFI1B gene to chromosome 9q34.13, distal of ABL1 (189980). This chromosomal region is translocated to chromosome 22q11 in chronic myeloid leukemia (151410).
Platelet-Type Bleeding Disorder 17
In affected members of a family with platelet-type bleeding disorder-17 (BDPLT17; 187900), originally reported by Kurstjens et al. (1968), Monteferrario et al. (2014) identified a heterozygous truncating mutation in the GFI1B gene (Q287X; 604383.0001). The mutation was found by linkage analysis followed by candidate gene sequencing. The patients had moderate recurrent bleeding and thrombocytopenia associated with decreased platelet alpha-granules and abnormal megakaryocytes on bone marrow biopsy. Myeloid and erythroid lineages were unaffected. The surface expression of several platelet markers, including alpha-2-beta integrin (ITGA2B; 607759), was normal, but 5 of 6 affected individuals had a marked decrease in the expression of platelet glycoprotein Ib-alpha (CD42B, GP1BA; 606672). Patient platelets also showed increased expression of CD34 (142230). In vitro functional expression studies showed that the mutant protein lacked transcriptional repression activity and acted in a dominant-negative manner when coexpressed with the wildtype protein. Expression of the mutation in mouse bone marrow cells resulted in dysplastic megakaryocytes with hypolobulated nuclei, irregular contours, and multiple separated nuclei, similar to the features observed in patient cells. The findings indicated that GFI1B has an important role in megakaryopoiesis and normal platelet production.
In affected members of a large family with BDPLT17, originally reported by Ardlie et al. (1976), Stevenson et al. (2013) identified a heterozygous truncating mutation in the GFI1B gene (604383.0002). In vitro cellular functional expression assays showed that the mutant protein was unable to repress the transcription of the target gene TGFBR3 (600742) or of itself, even when expressed with wildtype GFI1B. Patient platelets had decreased levels of the alpha-granule-related protein P-selectin (SELP; 173610), with smaller reductions in ITGB3 (173470) and GP1BA, compared to controls. These findings were associated with decreased alpha-granules observed by electron microscopy in patient platelets.
Ferreira et al. (2017) reported 2 unrelated patients with combined alpha-delta storage pool deficiency. The first, a 13-year-old boy, had a de novo heterozygous nonsense mutation in the GFI1B gene (604383.0003). The second, an 8-year-old boy, was homozygous for a missense mutation in the GFI1B gene (604383.0004).
GFI1B Polymorphisms
By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 individuals, followed by in silico replication in up to 52,024 independent samples, Polfus et al. (2016) found a significant association between a synonymous variant (Phe192; rs150813342) and low platelet count (minor allele frequency of 0.009, discovery and replication p = 1.79 x 10(-17)). CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells demonstrated that the variant affects splicing of exon 5 and suppresses formation of the long GFI1B isoform, which includes exon 5. This resulted in impaired megakaryocyte differentiation and platelet production. The SNP was not associated with mean platelet volume, platelet aggregation, or expression of platelet surface markers, and no significant effect was seen on circulating RBC levels. The findings suggested that the long isoform of GFI1B is necessary for normal megakaryocyte differentiation. Heterozygous carriers of the synonymous exon 5 variant in GFI1B had an average platelet count that is reduced by 25,000 to 30,000 platelets per microliter, which would be a clinically detectable effect.
Saleque et al. (2002) found that Gfi1b +/- mice appeared normal, but Gfi1b -/- embryos exhibited embryonic lethality. Livers of Gfi1b -/- embryos contained erythroid and megakaryocytic precursors arrested in their development, and many primitive erythrocytes were characterized by extensive membrane blebbing and ruffling. Myelopoiesis was normal. Gfi1b -/- embryos appeared to die during the transition from primitive to definitive hematopoiesis, with failure to produce enucleated erythrocytes. Saleque et al. (2002) concluded that GFI1B is an essential transcriptional regulator of erythroid and megakaryocyte development.
In affected members of a large family with autosomal dominant platelet-type bleeding disorder-17 (BDPLT17; 187900), originally reported by Kurstjens et al. (1968), Monteferrario et al. (2014) identified a heterozygous c.859C-T transition in exon 6 of the GFI1B gene, resulting in a gln287-to-ter (Q287X) substitution in zinc finger 5, which is required for DNA binding. The mutation was found by linkage analysis followed by candidate gene sequencing and segregated with the disorder in the family. A mutant transcript was detected in patient cells, indicating that the mutation did not cause nonsense-mediated mRNA decay. In vitro functional expression studies showed that the mutant protein lacked transcriptional repression activity and acted in a dominant-negative manner when coexpressed with the wildtype protein. Expression of the mutation in mouse bone marrow cells resulted in dysplastic megakaryocytes with hypolobulated nuclei, irregular contours, and multiple separated nuclei, similar to the features observed in patient cells.
In affected members of a large family with BDPLT17 (187900) originally reported by Ardlie et al. (1976), Stevenson et al. (2013) identified a heterozygous 1-bp insertion (c.880_881insC) in exon 7 of the GFI1B gene, resulting in a frameshift and premature termination (His294fsTer307) predicted to disrupt the fifth and sixth zinc finger DNA-binding domains. The mutation segregated with the disorder in the family and was not present in the 1000 Genomes Project database. Both wildtype and mutant transcript were detected in patient cells and platelets. In vitro cellular functional expression assays showed that the mutant protein was unable to repress the transcription of the target gene TGFBR3 (600742) or of itself, even when expressed with wildtype GFI1B. Patient platelets had decreased levels of the alpha-granule-related protein P-selectin (SELP; 173610), with smaller reductions in ITGB3 (173470) and GP1BA (606672), compared to controls. These findings were associated with decreased alpha-granules observed by electron microscopy in patient platelets.
In a 13-year-old boy with alpha-delta storage pool deficiency (BDPLT17; 187900), Ferreira et al. (2017) identified a de novo nonsense variant, c.793A-T (c.793A-T, NM_004188.5) in exon 5 of the GFI1B gene that resulted in premature termination of the protein at lys265 (lys265 to ter; K265X). The mutation disrupted the fourth zinc finger motif, but the transcript was predicted to avoid nonsense-mediated decay. This variant was not present in the ExAC database.
In an 8-year-old Mexican boy with spontaneous petechiae and thrombocytopenia (BDPLT17; 187900), Ferreira et al. (2017) identified a homozygous missense mutation in exon 6 of the GFI1B gene, c.923T-C (c.923T-C, NM_004188.5), that created a leucine-to-proline substitution at codon 308 (L308P). This variant occurred at a highly conserved residue in the sixth zinc finger motif. It was present in only 1 of 121,194 alleles in the ExAC database, specifically in 1 of 11,570 alleles from the Latino population. No functional data were presented.
Ardlie, N. G., Coupland, W. W., Schoefl, G. I. Hereditary thrombocytopathy: a familial bleeding disorder due to impaired platelet coagulant activity. Aust. New Zeal. J. Med. 6: 37-45, 1976. [PubMed: 1065298] [Full Text: https://doi.org/10.1111/j.1445-5994.1976.tb03289.x]
Ferreira, C. R., Chen, D., Abraham, S. M., Adams, D. R., Simon, K. L., Malicdan, M. C., Markello, T. C., Gunay-Aygun, M., Gahl, W. A. Combined alpha-delta platelet storage pool deficiency is associated with mutations in GFI1B. Molec. Genet. Metab. 120: 288-294, 2017. [PubMed: 28041820] [Full Text: https://doi.org/10.1016/j.ymgme.2016.12.006]
Kurstjens, R., Bolt, C., Vossen, M., Haanen, C. Familial thrombopathic thrombocytopenia. Brit. J. Haemat. 15: 305-317, 1968. [PubMed: 5681484] [Full Text: https://doi.org/10.1111/j.1365-2141.1968.tb01541.x]
Monteferrario, D., Bolar, N. A., Marneth, A. E., Hebeda, K. M., Bergevoet, S. M., Veenstra, H., Laros-van Gorkom, B. A. P., MacKenzie, M. A., Khandanpour, C., Botezatu, L., Fransen, E., Van Camp, G., and 11 others. A dominant-negative GFI1B mutation in the gray platelet syndrome. New Eng. J. Med. 370: 245-253, 2014. Note: Erratum: New Eng. J. Med. 373: 782 only, 2015. [PubMed: 24325358] [Full Text: https://doi.org/10.1056/NEJMoa1308130]
Northcott, P. A., Lee, C., Zichner, T., Stutz, A. M., Erkek, S., Kawauchi, D., Shih, D. J. H., Hovestadt, V., Zapatka, M., Sturm, D., Jones, D. T. W., Kool, M., and 67 others. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511: 428-434, 2014. [PubMed: 25043047] [Full Text: https://doi.org/10.1038/nature13379]
Polfus, L. M., Khajuria, R. K., Schick, U. M., Pankratz, N., Pazoki, R., Brody, J. A., Chen, M.-H., Auer, P. L., Floyd, J. S., Huang, J., Lange, L., van Rooij, F. J. A., and 44 others. Whole-exome sequencing identifies loci associated with blood cell traits and reveals a role for alternative GFI1B splice variants in human hematopoiesis. Am. J. Hum. Genet. 99: 481-488, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 785 only, 2016. [PubMed: 27486782] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.016]
Rodel, B., Wagner, T., Zornig, M., Niessing, J., Moroy, T. The human homologue (GFI1B) of the chicken GFI gene maps to chromosome 9q34.13--a locus frequently altered in hematopoietic diseases. Genomics 54: 580-582, 1998. [PubMed: 9878267] [Full Text: https://doi.org/10.1006/geno.1998.5601]
Saleque, S., Cameron, S., Orkin, S. H. The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev. 16: 301-306, 2002. [PubMed: 11825872] [Full Text: https://doi.org/10.1101/gad.959102]
Saleque, S., Kim, J., Rooke, H. M., Orkin, S. H. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Molec. Cell 27: 562-572, 2007. [PubMed: 17707228] [Full Text: https://doi.org/10.1016/j.molcel.2007.06.039]
Stevenson, W. S., Morel-Kopp, M.-C., Chen, Q., Liang, H. P., Bromhead, C. J., Wright, S., Turakulov, R., Ng, A. P., Roberts, A. W., Bahlo, M.., Ward, C. M. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J. Thromb. Haemost. 11: 2039-2047, 2013. [PubMed: 23927492] [Full Text: https://doi.org/10.1111/jth.12368]
Tong, B., Grimes, H. L., Yang, T.-Y., Bear, S. E., Qin, Z., Du, K., El-Deiry, W. S., Tsichlis, P. N. The Gfi-1B proto-oncoprotein represses p21(WAF1) and inhibits myeloid cell differentiation. Molec. Cell. Biol. 18: 2462-2473, 1998. [PubMed: 9566867] [Full Text: https://doi.org/10.1128/MCB.18.5.2462]