Alternative titles; symbols
HGNC Approved Gene Symbol: SOS2
Cytogenetic location: 14q21.3 Genomic coordinates (GRCh38) : 14:50,117,130-50,231,882 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q21.3 | Noonan syndrome 9 | 616559 | Autosomal dominant | 3 |
The Drosophila 'Son of sevenless' (Sos) gene was isolated by Simon et al. (1991) in a screen to identify components of the regulatory pathway between tyrosine kinase and the RAS G-proteins (e.g., 190020). Sos acts by catalyzing the exchange of GDP for GTP on ras.
Bowtell et al. (1992) isolated 2 cDNAs, designated Sos1 (182530) and Sos2, from a mouse eye library by screening with a probe from the Drosophila Sos gene. The partial Sos2 cDNA encoded a predicted 1297-amino acid protein which was 67% identical to the mouse Sos1 sequence. Both Sos1 and Sos2 had an overall amino acid identity of 45% with the Drosophila gene product. Northern blots showed that both genes are expressed in a wide variety of tissues and cell lines.
Webb et al. (1993) mapped Sos2 to mouse chromosome 12C3.3-D by interspecific backcross analysis and in situ hybridization. They mapped the human SOS2 homolog to 14q21 by in situ hybridization.
In a Brazilian mother and daughter with Noonan syndrome-9 (NS9; 616559), Yamamoto et al. (2015) identified a heterozygous missense mutation in the SOS2 gene (T376S; 601247.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. A different de novo heterozygous missense mutation (M267K; 601247.0002) was identified in a Brazilian patient with sporadic occurrence of the disorder. The 2 probands were from a cohort of 50 Brazilian patients with Noonan syndrome who underwent whole-exome sequencing and thus accounted for 4% of patients in this cohort. However, there was no statistical difference between the frequency of SOS2 variants identified in the patients (2 of 50) compared to variants identified in controls (3 of 107). The T376S mutation was subsequently found in an affected mother and daughter from a second family from the United States with Noonan syndrome. Functional studies of the variants were not performed. Yamamoto et al. (2015) hypothesized that mutations in SOS2 cause Noonan syndrome through a mechanism similar to that of SOS1 (182530), which causes NS4 (610733): a gain of function resulting in enhanced signaling and upregulation of the RAS/MAPK pathway.
In a Brazilian mother and daughter (family BR-F1) with Noonan syndrome (616559), Yamamoto et al. (2015) identified a heterozygous c.1127C-G transversion (c.1127C-G, NM_006939.2) in exon 9 of the SOS2 gene, resulting in a thr376-to-ser (T376S) substitution in the DH domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. The same T376S mutation was subsequently found in a mother and daughter (family US-F1) with Noonan syndrome from the United States. Functional studies of the variant were not performed.
In a Brazilian man (family BR-F2) with Noonan syndrome-9 (NS9; 616559), Yamamoto et al. (2015) identified a de novo heterozygous c.800T-A transversion (c.800T-A, NM_006939.2) in exon 6 the SOS2 gene, resulting in a met267-to-lys (M267K) substitution in the DH domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 609 Brazilian controls. Functional studies of the variant were not performed, but Yamamoto et al. (2015) noted that a mutation in the homologous residue in the SOS1 gene (M269R; 182530.0003) had been found in patients with Noonan syndrome-4 (NS4; 610733).
Bowtell, D., Fu, P., Simon, M. A., Senior, P. Identification of murine homologues of the Drosophila Son of sevenless gene: potential activators of ras. Proc. Nat. Acad. Sci. 89: 6511-6515, 1992. [PubMed: 1631150] [Full Text: https://doi.org/10.1073/pnas.89.14.6511]
Simon, M. A., Bowtell, D. D. L., Dodson, G. S., Laverty, T. R., Rubin, G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signalling by the sevenless protein tyrosine kinase. Cell 67: 701-716, 1991. [PubMed: 1934068] [Full Text: https://doi.org/10.1016/0092-8674(91)90065-7]
Webb, G. C., Jenkins, N. A., Largaespada, D. A., Copeland, N. G., Fernandez, C. S., Bowtell, D. D. L. Mammalian homologues of the Drosophila Son of sevenless gene map to murine chromosomes 17 and 12 and to human chromosomes 2 and 14, respectively. Genomics 18: 14-19, 1993. [PubMed: 8276400] [Full Text: https://doi.org/10.1006/geno.1993.1421]
Yamamoto, G. L., Aguena, M., Gos, M., Hung, C., Pilch, J., Fahiminiya, S., Abramowicz, A., Cristian, I., Buscarilli, M., Naslavsky, M. S., Malaquias, A. C., Zatz, M., Bodamer, O., Majewski, J., Jorge, A. A. L., Pereira, A. C., Kim, C. A., Passos-Bueno, M. R., Bertola, D. R. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J. Med. Genet. 52: 413-421, 2015. [PubMed: 25795793] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103018]