Alternative titles; symbols
HGNC Approved Gene Symbol: SPIDR
Cytogenetic location: 8q11.21 Genomic coordinates (GRCh38) : 8:47,260,878-47,736,306 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q11.21 | Ovarian dysgenesis 9 | 619665 | Autosomal recessive | 3 |
SPIDR is a nuclear scaffolding protein that functions in the repair of DNA double-strand breaks via homologous recombination (Wan et al., 2013).
By sequencing clones obtained from a human KG-1 cell line cDNA library, Nagase et al. (1995) cloned SPIDR, which they designated KIAA0146. The deduced 918-amino acid protein has an ATP/GTP-binding site motif A (P-loop) and a putative mitochondrial carrier motif. Northern blot analysis detected SPIDR expression in all 16 human tissues and 2 cell lines examined.
Wan et al. (2013) stated that the SPIDR protein contains 915 amino acids and has a predicted molecular mass of 105 kD.
By PCR of a human-rodent hybrid panel, Nagase et al. (1995) mapped the SPIDR gene to chromosome 8.
Hartz (2013) mapped the SPIDR gene to chromosome 8q11.21 based on an alignment of the SPIDR sequence (GenBank D63480) with the genomic sequence (GRCh37).
By coimmunoprecipitation analysis of human 293T cells, Yuan and Chen (2013) found that KIAA0146 interacted with FIGNL1 (613583), a protein that functions with RAD51 (179617) in DNA repair via homologous recombination. Both KIAA0146 and FIGNL1 were recruited to sites of DNA damage. Knockdown of KIAA0146 or deletion of the KIAA0146-binding region of FIGNL1 resulted in defective homologous recombination repair. Use of knockout mouse embryonic fibroblasts showed that the DNA damage response by Fignl1 and Kiaa0146 also required Mdc1 (607593), Rnf8 (611685), and ser139-phosphorylated histone H2ax (601772). FIGNL1 and KIAA0146 appeared to function in a DNA repair pathway that was independent of another RAD51-interacting protein, RAD51AP1 (603070).
Using protein interaction assays with human cell lines and expression constructs, Wan et al. (2013) showed that endogenous SPIDR interacted directly with BLM (RECQL3; 604610), a DNA helicase that assures high-fidelity repair of damaged DNA via homologous recombination. Both proteins colocalized to nuclear foci following DNA damage in HeLa cells. Knockdown of either SPIDR or BLM via small interfering RNA resulted in increased frequency of sister chromatid exchange following DNA damage and impaired RAD51 focus formation. Coimmunoprecipitation experiments showed that SPIDR interacted in a ternary complex with RAD51 and BLM. Knockdown of SPIDR in HeLa cells reduced the association of BLM with RAD51 and increased the number of chromosomal aberrations and cell sensitivity to DNA damage. Wan et al. (2013) concluded that SPIDR provides a link between BLM and the homologous recombination machinery.
In 2 Israeli Muslim Arab sisters with ovarian dysgenesis (ODG9; 619665), Smirin-Yosef et al. (2017) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the SPIDR gene (W280X; 615384.0001) that segregated with disease and was not found in public variant databases.
In a 16-year-old Indian girl with ODG9, Heddar et al. (2022) identified homozygosity for a nonsense variant in the SPIDR gene (R272X; 615384.0002) that segregated with disease and was present at very low minor allele frequency in public variant databases, only in heterozygosity. Functional analysis demonstrated an increase in chromosomal instability in patient cells, and the authors recommended long-term follow-up to monitor for the development of tumors or cancers.
In 2 Israeli Muslim Arab sisters with ovarian dysgenesis (ODG9; 619665), Smirin-Yosef et al. (2017) identified homozygosity for a c.839G-A transition (c.839G-A, NM_001080394.2) in the SPIDR gene, resulting in a trp280-to-ter (W280X) substitution. The mutation, which was present in heterozygosity in the unaffected parents and a healthy brother, was not found in public variant databases, including ExAC, or in homozygous state in 252 Muslim Arab individuals. Analysis of homologous recombination (HR) showed increased HR in peripheral blood lymphocytes from the sisters compared to those from their unaffected brother, consistent with elevated sister chromatid exchanges. Analysis of the DNA-binding protein 53PB1 (TP53BP1; 605230) and the DNA damage marker gamma-H2AX (H2AFX; 601772) in irradiated cells showed increased accumulation of 53PB1 but not gamma-H2AX in patient cells compared to controls. However, the authors noted that basal DNA damage levels in patient cells, as indicated by gamma-H2AX foci in untreated cells, were significantly elevated by an average of 2.8-fold compared to control cells.
In a 16-year-old Indian girl with ovarian dysgenesis (ODG9; 619665), Heddar et al. (2022) identified homozygosity for a c.814C-T transition (c.814C-T, NM_001080394) in exon 7 of the SPIDR gene, resulting in an arg272-to-ter (R272X) substitution. Her consanguineous parents were heterozygous for the mutation, which was present at low minor allele frequency in the gnomAD and Kaviar databases (3.68 x 10(-5) and 3.22 x 10(-5), respectively), only in heterozygous state. Patient cells demonstrated a marked increase in mitomycin-induced chromosomal breaks compared to wildtype cells.
Hartz, P. A. Personal Communication. Baltimore, Md. 8/27/2013.
Heddar, A., Guichoux, N., Auger, N., Misrahi, M. A SPIDR homozygous nonsense pathogenic variant in isolated primary ovarian insufficiency with chromosomal instability. Clin. Genet. 101: 242-246, 2022. [PubMed: 34697795] [Full Text: https://doi.org/10.1111/cge.14080]
Nagase, T., Seki, N., Tanaka, A., Ishikawa, K., Nomura, N. Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. [PubMed: 8590280] [Full Text: https://doi.org/10.1093/dnares/2.4.167]
Smirin-Yosef, P., Zuckerman-Levin, N., Tzur, S., Granot, Y., Cohen, L., Sachsenweger, J., Borck, G., Lagovsky, I., Salmon-Divon, M., Wiesmuller, L., Basel-Vanagaite, L. A biallelic mutation in the homologous recombination repair gene SPIDR is associated with human gonadal dysgenesis. J. Clin. Endocr. Metab. 102: 681-688, 2017. Note: Erratum: J. Clin. Endocr. Metab. 103: 364 only, 2018. [PubMed: 27967308] [Full Text: https://doi.org/10.1210/jc.2016-2714]
Wan, L., Han, J., Liu, T., Dong, S., Xie, F., Chen, H., Huang, J. Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair. Proc. Nat. Acad. Sci. 110: 10646-10651, 2013. [PubMed: 23509288] [Full Text: https://doi.org/10.1073/pnas.1220921110]
Yuan, J., Chen, J. FIGNL1-containing protein complex is required for efficient homologous recombination repair. Proc. Nat. Acad. Sci. 110: 10640-10645, 2013. [PubMed: 23754376] [Full Text: https://doi.org/10.1073/pnas.1220662110]