Alternative titles; symbols
HGNC Approved Gene Symbol: CLEC3B
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:45,026,303-45,036,071 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Macular dystrophy, retinal, 4 | 619977 | Autosomal dominant | 3 |
Tetranectin, a tetrameric protein isolated from human plasma, has 4 identical and noncovalently bound polypeptide chains, each of 181 amino acid residues. It has a specific binding affinity for sulfated polysaccharides and the kringle 4 of plasminogen. The plasma concentration of tetranectin is reduced in patients with various malignancies (summary by Berglund and Petersen, 1992).
Using a mixture of degenerate oligonucleotide probes, Berglund and Petersen (1992) isolated the gene for human tetranectin from a genomic library. The gene is about 12 kb and contains 2 intervening sequences. It encodes a 202-residue pretetranectin, with a signal peptide of 21 amino acid residues followed by the tetranectin sequence of 181 amino acid residues. Northern blot analysis demonstrated tetranectin mRNA in all 8 tissues tested, with the highest concentration in lung. Southern blot analysis demonstrated hybridization to 2 genes, but it was not determined whether these were allelic or nonallelic. Holtet et al. (1997) observed that tetranectin is, in fact, a homotrimer.
Zhou et al. (2022) investigated the expression of Clec3b in the mouse retina and found that the gene was highly expressed at embryonic day 13.5 and peaked at postnatal day 4, and then was constantly expressed in the mouse retina until adulthood.
Berglund and Petersen (1992) determined that the TNA gene spans about 12 kb and contains 3 exons.
Ibaraki et al. (1995) characterized mouse tetranectin and mapped the gene (Tna) to distal mouse chromosome 9 by analysis of 2 sets of multilocus crosses.
By PCR analysis of a panel of somatic cell hybrids containing cytogenetically defined regions of chromosome 3, Durkin et al. (1997) mapped the TNA gene to chromosome 3p22-p21.3. They quoted work by others indicating that the TNA cDNA sequence had been placed 175 cR from the most distal chromosome 3p marker on the radiation hybrid map of the Whitehead Institute/MIT Center for Genome Research.
Tetranectin is a plasminogen-binding protein that is induced during the mineralization phase of osteogenesis (Wewer et al., 1994). Thus, tetranectin is a candidate gene for human disorders affecting bone and connective tissue.
In affected individuals from 5 large multigenerational Japanese families living in the same small village, who had retinal macular degeneration (MCDR4; 619977) and were negative for mutation in known macular and retinal dystrophy genes, Zhou et al. (2022) identified heterozygosity for the same missense mutation in the CLEB3B gene (A180D; 187520.0001). The mutation segregated fully with disease in all 5 families, and was not found in public variant databases.
Using an adeno-associated virus vector, Zhou et al. (2022) overexpressed Clecb3 with the A180D (see 187520.0001) mutation in mouse retina and observed multiple subretinal hyperreflective deposits, as well as markedly reduced retinal thickness, particularly of the outer nuclear layer, compared to controls. These findings, including extensive retinal thinning, photoreceptor loss, and pigmentary subretinal deposits, were confirmed by OCT and histologic examination. The authors noted that these features were comparable to the late stages of the human A180D-associated phenotype. Full-field scotopic electroretinography at 1 month after injection revealed a 33% and 45% reduction in the a- and b-wave amplitudes, respectively, at maximum stimulus intensity in the Clec3B-A180D-injected eyes. Photopic responses, however, were not significantly different from control, indicating rod dysfunction. Measurement of visual function using optokinetic tracking showed a significantly lower spatial frequency in the mutant mice than controls, suggested functional vision deficits. Contrast sensitivity thresholds were compromised at high spatial frequencies, confirming decreased retinal function in the mutants.
In affected individuals from 5 Japanese families with retinal macular dystrophy-4 (MCDR4; 619977), Zhou et al. (2022) identified heterozygosity for a c.539C-A transversion (c.539C-A, NM_003278.3) in the CLEC3B gene, resulting in an ala180-to-asp (A180D) substitution at a conserved residue. The mutation segregated fully with disease in the 5 families, which were all from the same small village, and the variant was not found in the 1000 Genomes Project or gnomAD databases. Overexpression of the A180D Clec3b variant in mouse retina recapitulated the human phenotype, with extensive retinal thinning, photoreceptor loss, and pigmentary subretinal deposits, as well as reduced retinal function.
Berglund, L., Petersen, T. E. The gene structure of tetranectin, a plasminogen binding protein. FEBS Lett. 309: 15-19, 1992. [PubMed: 1511740] [Full Text: https://doi.org/10.1016/0014-5793(92)80729-z]
Durkin, M. E., Naylor, S. L., Albrechtsen, R., Wewer, U. M. Assignment of the gene for human Tetranectin (TNA) to chromosome 3p22-p21.3 by somatic cell hybrid mapping. Cytogenet. Cell Genet. 76: 39-40, 1997. [PubMed: 9154122] [Full Text: https://doi.org/10.1159/000134509]
Holtet, T. L., Graversen, J. H., Clemmensen, I., Thogersen, H. C., Etzerodt, M. Tetranectin, a trimeric plasminogen-binding C-type lectin. Protein Sci. 6: 1511-1515, 1997. [PubMed: 9232652] [Full Text: https://doi.org/10.1002/pro.5560060715]
Ibaraki, K., Kozak, C. A., Wewer, U. M., Albrechtsen, R., Young, M. F. Mouse tetranectin: cDNA sequence, tissue-specific expression, and chromosomal mapping. Mammalian Genome 6: 693-696, 1995. [PubMed: 8563165] [Full Text: https://doi.org/10.1007/BF00354289]
Wewer, U. M., Ibaraki, K., Schjorring, P., Durkin, M. E., Young, M. F., Albrechtsen, R. A potential role for tetranectin in mineralization during osteogenesis. J. Cell Biol. 127: 1767-1775, 1994. [PubMed: 7798325] [Full Text: https://doi.org/10.1083/jcb.127.6.1767]
Zhou, R., Mawatari, G., Cai, X.-B., Shen, R.-J., Wang, Y.-H., Wang, Y.-T., Guo, Y.-M., Guo, F.-Y., Yuan, J., Pan, D., Nao-i, N., Jin, Z.-B. CLEC3B is a novel causative gene for macular-retinal dystrophy. Genet. Med. 24: 1249-1260, 2022. [PubMed: 35331648] [Full Text: https://doi.org/10.1016/j.gim.2022.02.012]