Alternative titles; symbols
HGNC Approved Gene Symbol: MPIG6B
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38) : 6:31,720,296-31,726,714 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | ?Thrombocytopenia, anemia, and myelofibrosis | 617441 | Autosomal recessive | 3 |
G6B is an inhibitory receptor expressed on the surface of platelets (Newland et al., 2007). Members of the immunoglobulin (Ig) superfamily have at least 1 extracellular Ig domain, a transmembrane segment, and a cytoplasmic tail. In the case of inhibitory receptors, the cytoplasmic tail contains at least 1 ITIM (immunoreceptor tyrosine-based inhibitory motif) that possesses an SH2-binding domain. SH2 domain-containing protein-tyrosine phosphatases (e.g., SHP1, 176883, and SHP2, 176876) are recruited to the receptor, where they dephosphorylate membrane-bound phosphoproteins and modulate the signaling cascade (summary by de Vet et al., 2001).
By sequence analysis of a cosmid from the major histocompatibility complex (MHC) class III region, followed by screening of a fetal brain cDNA library, Ribas et al. (1999) identified the Ig superfamily member G6B. The deduced 241-amino acid G6B protein contains a leader sequence; an Ig domain with 4 cysteines; 2 putative N-glycosylation sites; a transmembrane region; an intracellular, proline-rich potential SH3-binding domain; and 2 putative phosphorylated tyrosine motifs, one of which has an SH2-binding domain and the other of which is common in mitogen-activated protein kinases. RT-PCR analysis failed to detect expression of G6B in activated and unactivated cell lines. Ribas et al. (1999) concluded that G6B may have a role in signal transduction.
Using nested RT-PCR, de Vet et al. (2001) detected expression of different sizes of G6B in the K562 erythroleukemia cell line and in Molt4 and Jurkat T-cell leukemia cell lines, but not in other cell lines tested. Sequence analysis indicated that there are both soluble and transmembrane isoforms of G6B. Western blot analysis showed that N-glycosidase F treatment leads to the expression of proteins of 18 to 24 kD. Immunofluorescence microscopy demonstrated plasma membrane expression of the G6B transmembrane isoforms and endoplasmic reticulum/Golgi expression of the G6B soluble proteins. Immunoprecipitation and immunoblot analysis revealed that a transmembrane isoform of G6B is phosphorylated and associated with SHP1 and SHP2.
Mazharian et al. (2012) found expression of the mouse G6b gene in mature bone marrow-derived megakaryocytes and platelets, but not in immature megakaryocytes.
Using RT-PCR, Western blot, and flow cytometric analyses, Newland et al. (2007) showed that G6B was expressed on platelets. G6B crosslinking inhibited platelet aggregation and activation in a calcium-independent manner. Newland et al. (2007) concluded that G6B is an inhibitory surface receptor on platelets and suggested that it may be an antithrombotic drug target.
Mazharian et al. (2012) found that human and mouse G6B were both constitutively tyrosine-phosphorylated; G6B was associated with SHP1 and SHP2 in mouse megakaryocytes and in mouse and human platelets.
By genomic sequence analysis, Ribas et al. (1999) determined that the G6B gene spans about 2 kb and contains 6 exons packed between 2 sets of repetitive elements.
By genomic sequence analysis, Ribas et al. (1999) mapped the G6B gene to the class III region of the MHC on 6p21.3.
In 4 sibs, born of consanguineous Arab parents, with thrombocytopenia, anemia, and myelofibrosis (THAMY; 617441), Melhem et al. (2016) identified a homozygous truncating mutation in the G6B gene (C108X; 606520.0001). The mutation was found by a combination of linkage analysis and exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family.
Mazharian et al. (2012) found that G6b-null mice developed macrothrombocytopenia and had a bleeding diathesis due to defective platelet production and function. Mutant mice showed increased platelet turnover and increased platelet clearance, including antibody-mediated clearance, associated with enlarged spleens, myelofibrosis, and extramedullary hematopoiesis. Bone marrow-derived mutant megakaryocytes showed reduced spreading and reduced branched proplatelets on fibrinogen- or fibronectin-coated surfaces compared to controls, suggesting defective outside-in integrin signaling and defective microtubule extension and actin-mediated branching. Mutant platelets had altered organelle and granule content, and both platelets and megakaryocytes had defective surface glycoprotein abundance. The findings indicated that G6B is a critical regulator of megakaryocyte function and platelet production.
In 4 sibs, born of consanguineous Arab parents, with thrombocytopenia, anemia, and myelofibrosis (THAMY; 617441), Melhem et al. (2016) identified a homozygous c.324C-A transversion in the G6B gene, resulting in a cys108-to-ter (C108X) substitution. The mutation was found by a combination of linkage analysis and exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in 134 in-house controls. Studies of patient cells and platelets were not performed. In vitro functional expression studies in K562 human chronic myelogenous leukemia cells showed that the mutant protein was unstable. Unlike the wildtype protein, the truncated protein was unable to enhance K562 differentiation into megakaryocytes and erythrocytes following stimulation.
de Vet, E. C. J. M., Aguado, B., Campbell, R. D. G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2. J. Biol. Chem. 276: 42070-42076, 2001. [PubMed: 11544253] [Full Text: https://doi.org/10.1074/jbc.M103214200]
Mazharian, A., Wang, Y.-J., Mori, J., Bem, D., Finney, B., Heising, S., Gissen, P., White, J. G., Berndt, M. C., Gardiner, E. E., Nieswandt, B., Douglas, M. R., Campbell, R. D., Watson, S. P., Senis, Y. A. Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function. Sci. Signal. 5: ra78, 2012. Note: Electronic Article. [PubMed: 23112346] [Full Text: https://doi.org/10.1126/scisignal.2002936]
Melhem, M., Abu-Farha, M., Antony, D., Al Madhoun, A., Bacchelli, C., Alkayal, F., AlKhairi, I., John, S., Alomari, M., Beales, P. L., Alsmadi, O. Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia. Europ. J. Haemat. 98: 218-227, 2016.
Newland, S. A., Macaulay, I. C., Floto, R. A., de Vet, E. C., Ouwehand, W. H., Watkins, N. A., Lyons, P. A., Campbell, R. D. The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro. Blood 109: 4806-4809, 2007. [PubMed: 17311996] [Full Text: https://doi.org/10.1182/blood-2006-09-047449]
Ribas, G., Neville, M., Wixon, J. L., Cheng, J., Campbell, R. D. Genes encoding three new members of the leukocyte antigen 6 superfamily and a novel member of Ig superfamily, together with genes encoding the regulatory nuclear chloride ion channel protein (hRNCC) and a N-omega-N-omega-dimethylarginine dimethylaminohydrolase homologue, are found in a 30-kb segment of the MHC class III region. J. Immun. 163: 278-287, 1999. [PubMed: 10384126]