Alternative titles; symbols
HGNC Approved Gene Symbol: SSBP1
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:141,738,321-141,750,488 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q34 | Optic atrophy 13 with retinal and foveal abnormalities | 165510 | Autosomal dominant | 3 |
SSBP1 is a housekeeping gene involved in mitochondrial biogenesis, including mtDNA replication and maintenance (summary by Tiranti et al., 1995; Jurkute et al., 2019). It is also a subunit of a single-stranded DNA (ssDNA)-binding complex involved in the maintenance of genome stability (Huang et al., 2009).
Tiranti et al. (1995) determined that the SSBP gene encodes a mitochondrial ssDNA-binding protein, which is also known as mtSSB. The mature SSBP product is a 132-amino acid protein.
Jurkute et al. (2019) found expression of the Ssbp1 gene in all layers of the mouse retina. In SH-SY5Y cells, SSBP1 colocalized with mitochondria and mitochondrial nucleoids.
Piro-Megy et al. (2020) found expression of the SSBP1 gene in human retinal ganglion cells, photoreceptors, and pigmented epithelium.
Tiranti et al. (1995) found that mature SSBP acted as a homotetramer to stabilize the displaced single strand of the normal and expanded displacement loop (D loop) during mtDNA replication, thus preventing formation of secondary single-stranded DNA structures, which could stop the gamma-DNA polymerase.
Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mtDNA genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that SSBP1 was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that SSBP1 copurified with mtDNA and was a core nucleoid protein. Bogenhagen et al. (2008) confirmed these findings by Western blot analysis.
Using HEK293 cells for tandem affinity purification, Huang et al. (2009) identified SOSSA (INTS3; 611347) and SOSSC (613273) as common components of 2 distinct and complementary ssDNA-binding heterotrimeric complexes defined by their inclusion of either SOSSB1 (SSBP1) or SOSSB2 (SSBP2; 607389), but not both. Coimmunoprecipitation analysis confirmed that SOSS complexes formed in HeLa cells independent of DNA damage. Recombinant heterotrimeric SOSS complexes specifically bound ssDNA, but not double-stranded DNA. SOSSA served as the central assembly factor, and SOSSB and SOSSC bound overlapping regions on SOSSA, but they did not interact directly with each other. Depletion of SOSSA by small interfering RNA led to dramatic decreases in SOSSB1 and SOSSB2 protein levels, abrogated targeting of SOSSB1 and SOSSB2 to chromatin, increased ionizing radiation sensitivity, caused defective G2/M checkpoint, and impaired homologous recombination repair. Huang et al. (2009) demonstrated that both SOSS complexes and the CTIP (RBBP8; 604124)/RPA (see RPA1; 179835) complex acted downstream of the MRE11 (600814)-RAD50 (604040)-NBS1 (NBN; 602667) complex and functioned in DNA damage repair.
By a PCR-based screening of a somatic cell hybrid panel and by fluorescence in situ hybridization, Tiranti et al. (1995) assigned the SSBP gene to 7q34.
In affected members of 2 unrelated families and in 2 additional unrelated patients with optic atrophy-13 with retinal and foveal abnormalities (OPA13; 165510), Jurkute et al. (2019) identified 3 different heterozygous missense mutations in the SSBP1 gene (R38Q, 600439.0001; R107Q, 600439.0002; and S141N, 600439.0003). The mutation in family 1 was found by a combination of linkage analysis and candidate gene sequencing; mutations in the other patients were found by Sanger sequencing of 31 probands with OPA. The variants segregated with the disorder in the 2 families; all were absent from the gnomAD database. Functional studies in zebrafish showed that all mutations caused a reduction in retinal atoh7 (609875) expression and acted in a dominant-negative manner. There was no evidence of mtDNA deletion in blood cells from patients in 2 families.
In 7 patients from 4 unrelated families with OPA13, Del Dotto et al. (2020) identified inherited or de novo heterozygous missense mutations in the SSBP1 gene (see, e.g., 600439.0002 and 600439.0004). The mutations were found by exome sequencing and the patients were identified through GeneMatcher. In vitro studies of patient fibroblasts showed mtDNA depletion, decreased ability to stimulate POLG1 (174763)-induced DNA synthesis, and variable defects in mitochondrial oxidative respiration. Expression of mutations into ssbp1-null zebrafish failed to rescue the abnormal optic nerve phenotype, suggesting that they cause a loss of function.
In affected members of a large multigenerational French family (family A) and in affected individuals from a 3-generation German family (family B) with OPA13, Piro-Megy et al. (2020) identified heterozygosity for the R38Q mutation in the SSBP1 gene. The mutation in family A, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation also segregated with the disorder in the German family. Direct screening of the SSBP1 gene identified 3 additional probands (families C, D, and E) with OPA13 who carried the heterozygous R107Q mutation in SSBP1. Fibroblasts derived from 3 patients from family A showed markedly reduced SSBP1 protein levels, suggesting that the mutation causes protein instability. Ultrastructural examination of patient fibroblasts showed abnormal mitochondrial structure with swelling and disorganized cristae, mtDNA depletion, impaired mtDNA synthesis, and decreased POLG1 levels compared to controls. However, mitochondrial respiration was not significantly decreased compared to controls.
Associations Pending Confirmation
For discussion of a possible association between biallelic variation in the SSBP1 gene and a systemic mitochondrial disorder, see 600439.0005.
Jurkute et al. (2019) found that morpholino knockdown of the ssbp1 gene in zebrafish resulted in a thin optic nerve, compromised neuronal specification in photoreceptor cells, and impaired differentiation of retinal ganglion cells. These abnormalities were associated with decreased expression of the developmental regulatory gene atoh7 (609875) in retinal ganglion cell precursors.
In 4 related patients (family 2) and in an unrelated individual (family 3) with optic atrophy-13 with retinal and foveal abnormalities (OPA13; 165510), Jurkute et al. (2019) identified a heterozygous c.113G-A transition (c.113G-A, NM_001256510.1) in exon 4 of the SSBP1 gene, resulting in an arg38-to-gln (R38Q) substitution at a conserved residue in the SSB domain. The mutation, which was found by Sanger sequencing, segregated with the disorder in family 2. The mutation was not present in the gnomAD database. Functional studies in zebrafish showed that the R38Q mutation caused a reduction in retinal atoh7 (609875) expression and acted in a dominant-negative manner. There was no evidence of mtDNA deletion in blood cells from the patient in family 3.
In multiple affected members of a 7-generation French family (family A) with OPA13, Piro-Megy et al. (2020) identified a heterozygous R38Q mutation in the SSBP1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There was evidence of age-dependent penetrance. Direct screening of the SSBP1 gene in additional probands identified 4 affected individuals in a 3-generation German OPA family (family B) with the R38Q mutation. Fibroblasts derived from 3 patients from family A showed markedly reduced SSBP1 protein levels, suggesting that the mutation causes protein instability. Ultrastructural examination of patient fibroblasts showed abnormal mitochondrial structure with swelling and disorganized cristae, mtDNA depletion, impaired mtDNA synthesis, and decreased POLG1 (174763) levels compared to controls. However, mitochondrial respiration was not significantly decreased.
In multiple affected members of a large multigenerational kindred (family 1) with optic atrophy-13 with retinal and foveal abnormalities (OPA13; 165510), Jurkute et al. (2019) identified a heterozygous c.320G-A transition (c.320G-A, NM_001256510.1) in exon 6 of the SSBP1 gene, resulting in an arg107-to-gln (R107Q) substitution at a conserved residue in the SSB domain. The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies in zebrafish showed that the R107Q mutation caused a reduction in retinal atoh7 (609875) expression and acted in a dominant-negative manner. There was no evidence of mtDNA deletions in blood samples in this family.
In an Italian father and son (family 1) with OPA13, Del Dotto et al. (2020) identified a heterozygous R107Q mutation in the SSBP1 gene. The mutation, which was found by exome sequencing, arose de novo in the father. Western blot analysis of patient fibroblasts showed that levels of the R107Q mutant were similar to controls. However, in vitro protein crosslinking experiments showed that the R107Q variant interfered with SSBP1 multimerization. Patient fibroblasts showed significant mtDNA depletion, decreased ability to stimulate POLG1-induced mtDNA synthesis, and a decreased mitochondrial oxidative respiratory rate compared to controls, all of which were consistent with mitochondrial dysfunction. Expression of the R107Q mutation into ssbp1-null zebrafish failed to rescue the abnormal optic nerve phenotype, suggesting that the mutation causes a loss of function.
In 3 probands (families C, D, and E) with OPA13, Piro-Megy et al. (2020) identified a heterozygous R107Q mutation of the SSBP1 gene. The mutations was found by direct screening of the gene. Segregation studies in the families and functional studies of the variant were not performed.
In a 45-year-old man (family 4) with optic atrophy-13 with retinal and foveal abnormalities (OPA13; 165510), Jurkute et al. (2019) identified a heterozygous c.422G-A transition (c.422G-A, NM_001256510.1) in exon 7 of the SSBP1 gene, resulting in a ser141-to-asn (S141N) substitution at a conserved residue in the SSB domain. The mutation was found by Sanger sequencing; DNA from the unaffected parents was not available for segregation studies. The mutation was not present in the gnomAD database. Functional studies in zebrafish showed that the S141N mutation caused a reduction in retinal atoh7 (609875) expression and acted in a dominant-negative manner. The patient had onset of optic atrophy in the second decade; detailed ophthalmologic studies were not reported.
In a woman (patient 3), born of unrelated parents (family 2), with optic atrophy-13 with retinal and foveal abnormalities (OPA13; 165510), Del Dotto et al. (2020) identified a de novo heterozygous c.119G-T transversion (c.119G-T, NM_003143.2) in the SSBP1 gene, resulting in a gly40-to-val (G40V) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Western blot analysis of patient fibroblasts showed that the G40V mutant had increased protein levels compared to controls. In vitro studies of patient fibroblasts showed mtDNA depletion, decreased ability to stimulate POLG1-induced DNA synthesis, and a partial defect in mitochondrial oxidative respiration. Expression of the G40V mutation into ssbp1-null zebrafish failed to rescue the abnormal optic nerve phenotype, suggesting that the mutation causes a loss of function.
This variant is classified as a variant of unknown significance because its contribution to a systemic mitochondrial disorder has not been confirmed.
In a 32-year-old man, born of unrelated Austrian parents (family 5), with a systemic mitochondrial disorder, Del Dotto et al. (2020) identified a homozygous c.394A-G transition (c.394A-G, NM_003143.2) in the SSBP1 gene, resulting in an ile132-to-val (I132V) substitution. The mutation was present in heterozygous state at a low frequency in the gnomAD database. Western blot analysis of patient fibroblasts showed that the I132V mutant showed significantly decreased protein levels compared to controls. Further studies of patient fibroblasts showed mtDNA depletion, mildly impaired mtDNA replication, and reduced ability to stimulate POLG1-induced mtDNA synthesis. Patient fibroblasts did not show a reduction of OXPHOS subunits or a decrease in mitochondrial oxygen consumption rate, although skeletal muscle biopsy showed COX-negative fibers and decreased activity of complexes I and III. Del Dotto et al. (2020) concluded that the I132V variant is a hypomorphic allele and only causes disease in the homozygous state. At age 4 years, the patient presented with unsteady gait and clumsy hand coordination. He had progressive sensorineural hearing loss and retinitis pigmentosa leading to blindness and deafness in early adulthood. He was ambulant with ataxia. He also had recurrent migraine headaches, hypertrophic cardiomyopathy, and progressive impaired renal function resulting in chronic renal failure. Cognition was moderately impaired, but he was able to live a social life within his family. Laboratory studies showed increased serum creatine kinase.
Bogenhagen, D. F., Rousseau, D., Burke, S. The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 283: 3665-3675, 2008. [PubMed: 18063578] [Full Text: https://doi.org/10.1074/jbc.M708444200]
Del Dotto, V., Ullah, F., Di Meo, I., Magini, P., Gusic, M., Maresca, A., Caporali, L., Palombo, F., Tagliavini, F., Baugh, E. H., Macao, B., Szilagyi, Z., and 35 others. SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder. J. Clin. Invest. 130: 108-125, 2020. [PubMed: 31550240] [Full Text: https://doi.org/10.1172/JCI128514]
Huang, J., Gong, Z., Ghosal, G., Chen, J. SOSS complexes participate in the maintenance of genomic stability. Molec. Cell 35: 384-393, 2009. [PubMed: 19683501] [Full Text: https://doi.org/10.1016/j.molcel.2009.06.011]
Jurkute, N., Leu, C., Pogoda, H.-M., Arno, G., Robson, A. G., Nurnberg, G., Altmuller, J., Thiele, H., Motameny, S., Toliat, M. R., Powell, K., Hohne, W., Michaelides M., Webster, A. R., Moore, A. T., Hammerschmidt, M., Nurnberg, P., Yu-Wai-Man, P., Votruba, M. SSBP1 mutations in dominant optic atrophy with variable retinal degeneration. Ann. Neurol. 86: 368-383, 2019. [PubMed: 31298765] [Full Text: https://doi.org/10.1002/ana.25550]
Piro-Megy, C., Sarzi, E., Tarres-Sole, A., Pequignot, M., Hensen, F., Quiles, M., Manes, G., Chakraborty, A., Senechal, A., Bocquet, B., Cazevielle, C., Roubertie, A., and 13 others. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy. J. Clin. Invest. 130: 143-156, 2020. [PubMed: 31550237] [Full Text: https://doi.org/10.1172/JCI128513]
Tiranti, V., Rossi, E., Ruiz-Carrillo, A., Rossi, G., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis. Genomics 25: 559-564, 1995. [PubMed: 7789991] [Full Text: https://doi.org/10.1016/0888-7543(95)80058-t]