Alternative titles; symbols
HGNC Approved Gene Symbol: ZFAT
Cytogenetic location: 8q24.22 Genomic coordinates (GRCh38): 8:134,477,788-134,832,339 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.22 | {Autoimmune thyroid disease, susceptibility to, 3} | 608175 | 3 |
Within a narrowed region of susceptibility to autoimmune thyroid disease on chromosome 8q23-q24 (AITD3; 608175), Shirasawa et al. (2004) identified the ZFAT1 gene by extending expressed sequence tags (ESTs) from public databases by RACE and RT-PCR. The longest predicted protein product consists of 1,243 amino acids with 18 zinc finger repeat domains. RT-PCR expression analysis in human tissues revealed that ZFAT1 is strongly expressed in placenta, kidney, spleen, testis, and peripheral blood lymphocytes. A truncated splice variant (TRZFAT) was strongly expressed in placenta, ovary, and tonsil. The TRZFAT variant encodes an 846-amino acid protein with 11 zinc finger repeat domains. A small antisense transcript (SASZFAT), which Shirasawa et al. (2004) stated may be a noncoding RNA, consists of 939 nucleotides.
Shirasawa et al. (2004) determined that the ZFAT1 gene consists of 19 exons. The gene undergoes alternative splicing of exons 1, 2, 3, and 9b, with the truncated transcript TRZFAT containing only 10 exons due to a stop codon in exon 9b. The longest ZFAT1 transcript consists of 16 exons. The small antisense transcript SASZFAT is composed of sequences from exons 9a and 9b.
Shirasawa et al. (2004) identified the ZFAT1 gene within a narrowed region of susceptibility to autoimmune thyroid disease on chromosome 8q23-q24.
Using linkage and association analyses of over 500 autoimmune thyroiditis patients and controls, Shirasawa et al. (2004) found association of a single-nucleotide polymorphism (Ex9b-SNP10; 610931.0001) in the ZFAT1 gene with susceptibility to autoimmune thyroid disease showing linkage to chromosome 8q24 (AITD3; 608175). Ex9b-SNP10 falls into the 3-prime-untranslated region of truncated ZFAT1 (TRZFAT) and the promoter region of a small antisense transcript (SASZFAT). In peripheral blood lymphocytes, SASZFAT was exclusively expressed in CD19+ B cells, and expression levels of SASZFAT and TRZFAT seemed to correlate with the Ex9b-SNP10 T-associated ZFAT1 allele, inversely and positively, respectively. Shirasawa et al. (2004) concluded that Ex9b-SNP10 is critically involved in the regulation of SASZFAT expression in vitro, and this expression results in decreased expression of TRZFAT. Shirasawa et al. (2004) suggested that the SNP-associated ZFAT1 allele may play a critical role in B cell function by affecting the expression level of TRZFAT through regulating SASZFAT expression, and that this regulatory mechanism of SNPs might be involved in controlling susceptibility or resistance to human disease.
Tsunoda et al. (2010) found that Zfat1 +/- mice were viable, fertile, and indistinguishable from wildtype mice, whereas Zfat -/- mice suffered early embryonic lethality. Zfat -/- placenta showed abnormal development of the spongiotrophoblast layer at embryonic day 8.0, and Zfat -/- yolk sacs were bloodless at embryonic day 9.5, with reduced number of blood islands and impaired differentiation of hematopoietic progenitor cells. Defects in hematopoietic differentiation were associated with profound reductions in expression of the direct Zfat targets Tal1 (187040), Lmo2 (180385), and Gata1 (305371) and in Tal1 downstream genes.
Shirasawa et al. (2004) found association of a functional SNP in intron 9 of the ZGAT1 gene (Ex9b-SNP10) with susceptibility to autoimmune thyroid disease (AITD3; 608175) in 112 probands with AITD studied by Sakai et al. (2001), and confirmed the association in 515 affected individuals and 526 controls. All participants in both studies were Japanese. The T allele of Ex9b-SNP10 was associated with increased risk for AITD (dominant model: odds ratio = 1.7, p = 0.00009). Shirasawa et al. (2004) demonstrated that the Ex9b-SNP10 allele of ZFAT1 affected the expression levels of a small antisense transcript (SASZFAT) and a truncated splice variant (TRZFAT) in B cells, suggesting that the Ex9b-SNP10 allele plays critical roles in B cell function and thus might be involved in the etiology of AITD.
Sakai, K., Shirasawa, S., Ishikawa, N., Ito, K., Tamai, H., Kuma, K., Akamizu, T., Tanimura, M., Furugaki, K., Yamamoto, K., Sasazuki, T. Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Hum. Molec. Genet. 10: 1379-1386, 2001. [PubMed: 11440990] [Full Text: https://doi.org/10.1093/hmg/10.13.1379]
Shirasawa, S., Harada, H., Furugaki, K., Akamizu, T., Ishikawa, N., Ito, K., Ito, K., Tamai, H., Kuma, K., Kubota, S., Hiratani, H., Tsuchiya, T., Baba, I., Ishikawa, M., Tanaka, M., Sakai, K., Aoki, M., Yamamoto, K., Sasazuki, T. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Hum. Molec. Genet. 13: 2221-2231, 2004. [PubMed: 15294872] [Full Text: https://doi.org/10.1093/hmg/ddh245]
Tsunoda, T., Takashima, Y., Tanaka, Y., Fujimoto, T., Doi, K., Hirose, Y., Koyanagi, M., Yoshida, Y., Okamura, T., Kuroki, M., Sasazuki, T., Shirasawa, S. Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands. Proc. Nat. Acad. Sci. 107: 14199-14204, 2010. [PubMed: 20660741] [Full Text: https://doi.org/10.1073/pnas.1002494107]