HGNC Approved Gene Symbol: SON
SNOMEDCT: 1169355000;
Cytogenetic location: 21q22.11 Genomic coordinates (GRCh38): 21:33,543,038-33,577,481 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.11 | ZTTK syndrome | 617140 | Autosomal dominant | 3 |
SON is a nuclear speckle-localized protein that shares homology with pre-mRNA splicing accessory factors (Wynn et al., 2000).
Berdichevskii et al. (1988) cloned a fragment designated Son3 from a human embryonic cDNA bank. The nucleotide sequence was found to be 1,454 bp long with 6 possible open reading frames, only 1 of which did not contain terminating codons. Translation of that open reading frame into an amino acid sequence and database analysis showed that the Son3 region codes for a protein with the following distinctive features: (1) the presence of a cluster of short tandem repeats from 7 to 19 amino acids long, located in the central part of the sequence; (2) the presence of lengthy regions of homology with certain DNA-binding structural proteins, such as gallin (55%), and also with oncoproteins encoded by protooncogenes of the MYC family; and (3) the presence of a region of homology with an oncoprotein encoded by the MOS protooncogene (190060).
Wynn et al. (2000) independently identified human SON, which shares 84.2% amino acid identity with its mouse homolog. SON has a basic serine/arginine-rich C-terminal domain that shares homology with proteins involved in mRNA processing. Immunofluorescence studies localized endogenous SON to interchromatin granules of the interphase nucleus in human epithelial cells. The nuclear speckled staining pattern was similar to that observed with mRNA splicing factors, suggesting that SON may play a role in mRNA processing.
From a human keratinocyte cDNA library, Khan et al. (1994) isolated a clone for the DNA-binding protein SON. Using this clone, they found that the SON gene is expressed in various cell types and that homologous sequences can be detected in vertebrate and insect genomic DNA.
Using a combination of proteomics, cytology, and functional analysis in C. elegans, Chu et al. (2006) reduced 1,099 proteins copurified with spermatogenic chromatin to 132 proteins for functional analysis. This strategy to find fertility factors conserved from C. elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins, 37% (7 of 19) cause male sterility. This list includes PPP1CC (176914), H2AX (601772), SON, TOP1 (126420), DDX4 (605281), DBY (400010), and CENPC (117141).
Karlas et al. (2010) reported the discovery of 287 human host cell genes influencing influenza A virus replication, including SON, in a genomewide RNA interference screen. Using an independent assay, Karlas et al. (2010) confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. SON was found to be important for normal trafficking of influenza virions to late endosomes early in infection.
Slavov et al. (2000) predicted that the SON gene contains 10 exons spanning 25 kb. Wynn et al. (2000) determined that the SON gene contains 12 exons.
Using PCR to amplify SON sequences from a panel of somatic cell hybrids, Khan et al. (1994) assigned the human SON gene to chromosome 21. By use of hybrids containing regions of chromosome 21, the localization was refined to 21q22.1-q22.2.
Wynn et al. (2000) determined that both human and mouse SON and DONSON (611428) are in tail-to-tail orientation and in the following order: GART (138440)-SON-DONSON.
In a 5-year-old girl with ZTTK syndrome (ZTTKS; 617140), Zhu et al. (2015) identified heterozygosity for a de novo 4-bp deletion (182465.0001) in the SON gene, resulting in a frameshift and premature termination.
In a 13-year-old boy with ZTTK syndrome, Takenouchi et al. (2016) identified heterozygosity for the same frameshift mutation in the SON gene that had been identified by Zhu et al. (2015).
In 20 unrelated patients with ZTTK syndrome (ZTTKS; 617140), including the patient (patient 3) reported by Zhu et al. (2015), Kim et al. (2016) identified de novo heterozygous truncating mutations in the SON gene (see, e.g., 182465.0001-182465.0004). The mutations were found by whole-exome sequencing; 4 patients carried the same frameshift mutation (182465.0001). Examination of cells from 3 of the patients with SON haploinsufficiency showed decreased mRNA expression and abnormal RNA splicing products of multiple genes that play a role in neuronal cell migration, brain development, and metabolism (e.g., FLNA, 300017 and TUBG1, 191135). Similar gene dysregulation was observed in HeLa cells with knockdown of the SON gene. The findings demonstrated that SON is a master RNA splicing regulator with an important role in neurodevelopment.
In 6 unrelated patients with ZTTKS, Tokita et al. (2016) identified de novo heterozygous truncating mutations in the SON gene (see, e.g., 182465.0001; 182465.0005-182465.0007). The patients were ascertained by whole-exome sequencing of over 6,000 patients, primarily children, with neurologic disorders. Two of the patients carried the recurrent frameshift mutation (182465.0001). A seventh patient with 2 de novo missense mutations in cis was subsequently identified. Functional studies of the variants and studies of patient cells were not performed, but the findings suggested that haploinsufficiency for the SON gene is responsible for the phenotype, which may represent a spliceosomal disorder.
Dingemans et al. (2022) reviewed data on the variants in the SON gene that were identified in 52 persons with ZTTK syndrome, including 49 predicted loss-of-function variants (40 frameshift variants, 5 nonsense variants, 2 in-frame deletions, and 2 whole-gene deletions) and 3 missense variants. Forty-nine mutations occurred de novo, whereas inheritance could not be determined for 3. The most common variant, leading to a frameshift (c.5753_5756delTTAG; 182465.0001), was found in 13 patients; however, overall the variants were spread across the gene. To evaluate whether missense variants have a similar mechanism to loss-of-function variants, which were shown to produce erroneous splicing of targeted genes, functional validation was performed on one patient with a missense variant. Dysregulation of splicing of downstream targets was not seen, suggesting that the underlying mechanism might be different in missense variants.
Kim et al. (2016) found that haploinsufficiency of the son gene in zebrafish embryos resulted in multiple developmental defects, including bent and shortened tails, eye malformations, microcephaly, and deformed body axes with body curvatures. Embryos that survived longer developed even more severe phenotypes including spinal malformations and brain edema.
In a 5-year-old girl (from trio 91) with ZTTK syndrome (ZTTKS; 617140), Zhu et al. (2015) identified heterozygosity for a de novo 4-bp deletion (ENST00000356577.4:c.5751_5754delAGTT) in the SON gene, resulting in a frameshift and premature termination (Val1918GlufsTer87).
In a 13-year-old boy with ZTTK syndrome, Takenouchi et al. (2016) identified heterozygosity for the same 4-bp deletion (c.5753_5756delTTAG, NM_138927.2) in the SON gene, resulting in a frameshift and premature termination (Val 1918GlufsTer87). The mutation occurred de novo.
Tokita et al. (2016) identified a de novo heterozygous c.5753_5756delTTAG mutation in 2 unrelated girls (patients 1 and 5) with ZTTKS. The mutations were found by whole-exome sequencing; the variant was not found in the ExAC database.
In 4 unrelated children (patients 3, 5, 18, 19) with ZTTK syndrome, including the patient (patient 3) reported by Zhu et al. (2015), Kim et al. (2016) identified heterozygosity for a de novo c.5753_5756delTTAG in exon 3 of the SON gene, resulting in a frameshift and premature termination within the RS domain. The mutation, which occurred de novo in all 4 children, was found by exome sequencing and was not found in over 2,000 control individuals. Peripheral blood cells derived from 2 patients showed significantly decreased levels of mutant transcript, consistent with haploinsufficiency.
In a review of molecular data on 52 patients with ZTTK syndrome, Dingemans et al. (2022) found that the most frequently occurring mutation in the SON gene was c.5753_5756delTTAG, which was found in 13 patients.
In a 5-year-old girl (patient 1) with ZTTK syndrome (ZTTKS; 617140), Kim et al. (2016) identified a de novo heterozygous 2-bp deletion (c.5549_5550del, NM_138927.2) in exon 3 of the SON gene, resulting in a frameshift and premature termination (Arg1850IlefsTer3) in the RS domain. The mutation, which was found by exome sequencing, was not found in over 2,000 control individuals. Peripheral blood cells derived from the patient patients showed significantly decreased levels of mutant transcript and protein, consistent with haploinsufficiency.
In a 6-year-old boy (patient 7) with ZTTK syndrome (ZTTKS; 617140), Kim et al. (2016) identified a de novo heterozygous 2-bp insertion (c.6002_6003insCC, NM_138927.2) in exon 3 of the SON gene, resulting in a frameshift and premature termination (Arg2002GlnfsTer5) in the RS domain. The mutation, which was found by exome sequencing, was not found in over 2,000 control individuals.
In a 7-year-old girl (patient 9) with ZTTK syndrome (ZTTKS; 617140), Kim et al. (2016) identified a de novo heterozygous 1-bp deletion (c.4640del, NM_138927.2) in exon 3 of the SON gene, resulting in a frameshift and premature termination (His1547LeufsTer76). The mutation, which was found by exome sequencing, was not found in over 2,000 control individuals.
In a 3-year-old girl (patient 4) with ZTTK syndrome (ZTTKS; 617140), Tokita et al. (2016) identified a de novo heterozygous c.286C-T transition (c.286C-T, NM_138927.2) in exon 3 of the SON gene, resulting in a gln96-to-ter (Q96X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
In a 9-year-old girl (patient 6) with ZTTK syndrome (ZTTKS; 617140), Tokita et al. (2016) identified a de novo heterozygous 1-bp duplication (c.3073dupA, NM_138927.2) in exon 3 of the SON gene, resulting in a frameshift and premature termination (Met1025AsnfsTer6). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
In a 23-year-old man (patient 7) with ZTTK syndrome (ZTTKS; 617140), Tokita et al. (2016) identified a de novo heterozygous 1-bp deletion (c.6233delC, NM_138927.2) in exon 4 of the SON gene, resulting in a frameshift and premature termination (Pro2078HisfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database.
Berdichevskii, F. B., Chumakov, I. M., Kiselev, L. L. Determination of the nucleotide sequence of the son3 fragment of the human genome: identification of a new protein with an unusual structure and homology with DNA-binding proteins. Molec. Biol. (Mosk) 22: 794-801, 1988. [PubMed: 3054499]
Chu, D. S., Liu, H., Nix, P., Wu, T. F., Ralston, E. J., Yates, J. R., III, Meyer, B. J. Sperm chromatin proteomics identifies evolutionarily conserved fertility factors. Nature 443: 101-105, 2006. [PubMed: 16943775] [Full Text: https://doi.org/10.1038/nature05050]
Dingemans, A. J. M., Truijen, K. M. G., Kim, J. H., Alacam, Z., Faivre, L., Collins, K. M., Gerkes, E. H., van Haelst, M., van de Laar, I. M. B. H., Lindstrom, K., Nizon, M., Pauling, J., and 13 others. Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. Europ. J. Hum. Genet. 30: 271-281, 2022. [PubMed: 34521999] [Full Text: https://doi.org/10.1038/s41431-021-00960-4]
Karlas, A., Machuy, N., Shin, Y., Pleissner, K.-P., Artarini, A., Heuer, D., Becker, D., Khalil, H., Ogilvie, L. A., Hess, S., Maurer, A. P., Muller, E., Wolff, T., Rudel, T., Meyer, T. F. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463: 818-822, 2010. [PubMed: 20081832] [Full Text: https://doi.org/10.1038/nature08760]
Khan, I. M., Fisher, R. A., Johnson, K. J., Bailey, M. E. S., Siciliano, M. J., Kessling, A. M., Farrer, M., Carritt, B., Kamalati, T., Buluwela, L. The SON gene encodes a conserved DNA binding protein mapping to human chromosome 21. Ann. Hum. Genet. 58: 25-34, 1994. [PubMed: 8031013] [Full Text: https://doi.org/10.1111/j.1469-1809.1994.tb00723.x]
Kim, J.-H., Shinde, D. N., Reijnders, M. R. F., Hauser, N. A., Belmonte, R. L., Wilson, G. R., Bosch, D. G. M., Bubulya, P. A., Shashi, V., Petrovski, S., Stone J. K., Park, E. Y., and 54 others. De novo mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome. Am. J. Hum. Genet. 99: 711-719, 2016. [PubMed: 27545680] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.029]
Slavov, D., Hattori, M., Sakaki, Y., Rosenthal, A., Shimizu, N., Minoshima, S., Kudoh, J., Yaspo, M.-L., Ramser, J., Reinhardt, R., Reimer, C., Clancy, K., Rynditch, A., Gardiner, K. Criteria for gene identification and features of genome organization: analysis of 6.5 Mb of DNA sequence from human chromosome 21. Gene 247: 215-232, 2000. [PubMed: 10773462] [Full Text: https://doi.org/10.1016/s0378-1119(00)00089-5]
Takenouchi, T., Miura, K., Uehara, T., Mizuno, S., Kosaki, K. Establishing SON in 21q22.11 as a cause a (sic) new syndromic form of intellectual disability: possible contribution to Braddock-Carey syndrome phenotype. Am. J. Med. Genet. 170A: 2587-2590, 2016. [PubMed: 27256762] [Full Text: https://doi.org/10.1002/ajmg.a.37761]
Tokita, M. J., Braxton, A. A., Shao, Y., Lewis, A. M., Vincent, M., Kury, S., Besnard, T., Isidor, B., Latypova, X., Bezieau, S., Liu, P., Motter, C. S., and 15 others. De novo truncating variants in SON cause intellectual disability, congenital malformations, and failure to thrive. Am. J. Hum. Genet. 99: 720-727, 2016. [PubMed: 27545676] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.035]
Wynn, S. L., Fisher, R. A., Pagel, C., Price, M., Liu, Q. Y., Khan, I. M., Zammit, P., Dadrah, K., Mazrani, W., Kessling, A., Lee, J. S., Buluwela, L. Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes. Genomics 68: 57-62, 2000. [PubMed: 10950926] [Full Text: https://doi.org/10.1006/geno.2000.6254]
Zhu, X., Petrovski, S., Xie, P., Ruzzo, E. K., Lu, Y.-F., McSweeney, M., Ben-Zeev, B., Nissenkorn, A., Anikster, Y., Oz-Levi, D., Dhindsa, R. S., Hitomi, Y., and 15 others. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 17: 774-781, 2015. [PubMed: 25590979] [Full Text: https://doi.org/10.1038/gim.2014.191]