Alternative titles; symbols
HGNC Approved Gene Symbol: SASH1
Cytogenetic location: 6q24.3-q25.1 Genomic coordinates (GRCh38): 6:148,193,468-148,552,044 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q24.3-q25.1 | ?Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma | 618373 | Autosomal recessive | 3 |
| Dyschromatosis universalis hereditaria 1 | 127500 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned SASH1, which they designated KIAA0790. The deduced protein contains 1,319 amino acids. RT-PCR ELISA detected moderate to high expression in all tissues examined, with highest expression in heart, brain, lung, ovary, and kidney.
By loss of heterozygosity and in silico expression analysis to identify genes on chromosome 6q23-q25 that are downregulated in breast cancers, Zeller et al. (2003) identified SASH1. They obtained the full-length cDNA by assembling SASH1 ESTs. The deduced 1,247-amino acid protein has a calculated molecular mass of about 140 kD. SASH1 contains 2 sterile alpha modules (SAMs) and an Src homology-3 (SH3) domain. These domains are predominantly found in signaling molecules, adaptors, and scaffold proteins. SASH1 also has an N-terminal 25-residue proline-rich sequence. The mRNA has a long 3-prime untranslated region that has 2 polyadenylation signals. The human and mouse SASH1 proteins share 85% homology. Northern blot analysis detected a 4.4-kb transcript that was expressed ubiquitously, with highest levels in lung, placenta, spleen, and thymus. A 7.5-kb transcript was detected at lower levels in all tissues surveyed except brain.
Using RT-PCR, Dauphinee et al. (2013) verified ubiquitous expression of Sash1 mNRA in mouse tissues. Gene-trap analysis showed that Sash1 was strongly expressed in the microvascular endothelium of all mouse organs examined.
Shellman et al. (2015) detected SASH1 expression in cultured human epidermal keratinocytes, dermal fibroblasts, and melanocytes.
Zeller et al. (2003) determined that the SASH1 gene contains 20 exons and spans about 210 kb.
By radiation hybrid analysis, Nagase et al. (1998) mapped the SASH1 gene to chromosome 6. Zeller et al. (2003) mapped the SASH1 gene to chromosome 6q24.3 by genomic sequence analysis.
By electronic Northern profiling of ESTs and RT-PCR analysis, Zeller et al. (2003) found significant downregulation of SASH1 in a majority of primary breast tumor tissues and breast cancer cell lines examined. All cell lines with deletions of chromosome 6q24.3 showed little to no SASH1 expression. Expression was reduced in 60% of breast tumors compared with normal breast tissue in a survey of 15 matched samples. A survey of 50 matched samples showed reduced expression in 74% of tumors. Expression was also reduced in a majority of lung and thyroid tumors, as well as in a few colon carcinomas. Zeller et al. (2003) did not identify mutations associated with primary breast cancers in the coding region of the SASH1 gene, and they hypothesized that other mechanisms, such as promoter methylation, may be responsible for loss of SAHS1 expression in primary and metastatic breast cancers.
By proteomic analysis of lipopolysaccharide (LPS)-stimulated mouse embryonic fibroblasts, Dauphinee et al. (2013) identified Sash1 as part of the Tlr4 (603030) signaling pathway. Knockdown of SASH1 in human microvascular endothelial cells decreased NFKB (see 164011) luciferase activity in response to LPS, but not in response to TLR2 (603028), TLR3 (603029), TLR5 (603031), or other TRAF6 (602355)-dependent receptors. SASH1 knockdown also resulted in decreased production of IL6 (147620) and IL10 (124092), but it did not affect interferon-regulated genes. Coimmunoprecipitation analysis showed that residues 852 to 860 of SASH1 bound to the C-terminal region of TRAF6 containing the coiled-coil domain and that the interaction depended on LPS. SASH1 did not interact with MYD88 (602170), IRAKs (e.g., IRAK1; 300283), or other TRAF molecules. Overexpression of SASH1, in the absence of stimulation, induced autoubiquitination of TRAF6 without direct interaction of SASH1 with ubiquitin-conjugating enzymes, such as UBC13 (603679). Further coimmunoprecipitation experiments showed that the large SASH1 molecule acted as a scaffold by binding TAK1 (MAP3K7; 602614) and the IKK complex molecules IKBKA (CHUK; 600664) and IKBKB (603258) to facilitate signaling to NFKB. SASH1 also regulated TAK1 ubiquitination and activation of the downstream MAPKs JNK1 (MAPK8; 601158) and p38 (MAPK14; 600289). Knockdown of SASH1 significantly reduced endothelial cell migration in response to LPS. Dauphinee et al. (2013) concluded that SASH1 is a novel regulator of TLR4 signaling through its formation of a molecular complex around TRAF6.
Using immunoprecipitation and Western blot analyses, Zhou et al. (2017) showed that human SASH1 interacted with G-alpha-s (139320) in transfected HEK293T cells. The authors identified a p53 (TP53; 191170)/POMC (176830)/alpha-MSH/G-alpha-S/SASH1 autoregulatory loop that regulated reciprocal induction between SASH1 and p53 during physiologic and pathophysiologic conditions.
Dyschromatosis Universalis Hereditaria 1
In affected individuals from 3 unrelated families with dyschromatosis (DUH1; 127500), Zhou et al. (2013, 2017) identified heterozygosity for 3 different missense mutations in the SASH1 gene (Y551D, 607955.0001; L515P, 607955.0002; and E509K, 607955.0003). The mutations segregated with disease in each family, respectively, and were not found in controls or public variant databases. Functional analysis indicated that the mutations cause upregulation of SASH1 expression, associated with increased transepithelial migration of melanocytes. SASH1 mutations also upregulated expression of p53 and POMC. Western blot analysis demonstrated that SASH1 mutations increased production of melanogenic components and induced heterogeneous distribution of melanin, resulting in pathologic hyperpigmentation.
In affected individuals from a large Hispanic family with multiple lentigines, Shellman et al. (2015) identified heterozygosity for a SASH1 missense mutation (S519N; 607955.0005) that segregated fully with disease and was not found in 150 ethnically matched controls or in public variant databases.
In 2 Chinese boys with multiple lentigines, Zhang et al. (2016) identified heterozygous SASH1 mutations: a missense mutation (S513R; 607955.0006) in patient 1, and a frameshift mutation (607955.0007) in patient 2. The authors noted that the 6 reported heterozygous mutations in patients with DUH1 cluster in the evolutionarily conserved SLY domain, suggesting a potential mutational hotspot region.
In a Chinese mother and son with multiple lentigines, Wang et al. (2017) identified heterozygosity for a SASH1 missense mutation (S507A; 607955.0008) that had arisen de novo in the mother. The authors stated that their findings further verified SASH1 as a causal gene of lentiginous phenotypes with or without dyschromatosis.
In 2 Chinese families with DUH, Zhong et al. (2019) screened the 3 dyschromatosis-associated genes and identified heterozygous missense mutations in SASH1 in affected members of both families: Y551H (607955.0009) and M595T (607955.0010). The authors noted that the latter mutation was the first in the SH3 domain to be reported.
Cancer, Alopecia, Pigment Dyscrasia, Onychodystrophy, and Keratoderma
In a Moroccan brother and sister with CAPOK syndrome (618373), Courcet et al. (2015) identified homozygosity for a missense mutation in the SASH1 gene (E617K; 607955.0004) that segregated with disease in the family and was not found in local exomes or public variant databases.
In affected members of a Chinese family (family I) with dyschromatosis universalis hereditaria (DUH1; 127500), Zhou et al. (2013, 2017) identified heterozygosity for a c.2126T-G transversion (c.2126T-G, NM_015278.3) in exon 14 of the SASH1 gene, resulting in a tyr551-to-asp (Y551D) substitution at a conserved residue. The mutation segregated fully with disease in the family and was not found in 500 controls or in public variant databases, including the HapMap database. By immunoblot analysis using transfected A375 cells, Zhou et al. (2013) observed upregulation of Y551D mutant SASH1; CHX treatment revealed that the mutant protein was more stable than wildtype. Immunohistochemistry of patient epithelial tissue showed distribution of SASH1 in almost all layers of the epidermis, in contrast to epithelium from unaffected individuals, in which SASH1-positive cells were concentrated in the basal layers. In addition, immunohistochemical identification of melanocytes (MCs) indicated an uneven distribution of MCs in the epithelial layers. Transwell migration assay demonstrated significantly higher numbers of invasive Y551D mutant cells, as well as higher numbers of migrating Y551D mutant cells, than wildtype cells. In addition, Zhou et al. (2013) found that the mutant showed enhanced binding with the cell-adhesion partners IQGAP1 (603379) and Gs-alpha (GNAS; 139320), and caused significant reduction of E-cadherin (CDH1; 192090) expression.
In affected members of a Chinese family (family II) with dyschromatosis universalis hereditaria (DUH1; 127500), Zhou et al. (2013, 2017) identified heterozygosity for a c.2019T-C transition (c.2019T-C, NM_015278.3) in exon 13 of the SASH1 gene, resulting in a leu515-to-pro (L515P) substitution at a conserved residue. The mutation segregated fully with disease in the family and was not found in 500 controls or in public variant databases, including the HapMap database. By immunoblot analysis using transfected A375 cells, Zhou et al. (2013) observed upregulation of L515P mutant SASH1; CHX treatment revealed that the mutant protein was more stable than wildtype. Transwell migration assay demonstrated significantly higher numbers of invasive L515P mutant cells, as well as higher numbers of migrating L515P mutant cells, than wildtype cells. In addition, Zhou et al. (2013) found that the mutant showed enhanced binding with the cell-adhesion partners IQGAP1 (603379) and Gs-alpha (GNAS; 139320), and caused significant reduction of E-cadherin (CDH1; 192090) expression.
In 3 affected members of an American family (family III) with dyschromatosis universalis hereditaria (DUH1; 127500), Zhou et al. (2013, 2017) identified heterozygosity for a c.2000G-A transition (c.2000G-A, NM_015278.3) in exon 13 of the SASH1 gene, resulting in a glu509-to-lys (E509K) substitution at a conserved residue. DNA was unavailable from unaffected family members for study, but the mutation was not found in 500 controls or in public variant databases, including the HapMap database. By immunoblot analysis using transfected A375 cells, Zhou et al. (2013) observed upregulation of E509K mutant SASH1; CHX treatment revealed that the mutant protein was more stable than wildtype. In addition, Zhou et al. (2013) found that the mutant showed enhanced binding with the cell-adhesion partners IQGAP1 (603379) and Gs-alpha (GNAS; 139320), and caused significant reduction of E-cadherin (CDH1; 192090) expression.
In a Moroccan brother and sister with alopecia, dyschromatosis, nail dystrophy, palmoplantar keratoderma, and squamous cell carcinomas (CAPOK; 618373), Courcet et al. (2015) identified homozygosity for a c.1849G-A transition (c.1849G-A, NM_015278.3) in the SASH1 gene, resulting in a glu617-to-lys (E617K) substitution at a well-conserved residue. Their unaffected parents and an unaffected brother were heterozygous for the mutation, which was not found in 245 local exomes or in the Exome Variant Server or dbSNP135 databases. A wound-healing assay demonstrated that patient fibroblasts migrated better into the wound than control fibroblasts.
In 17 affected members of a large Hispanic family with nonsyndromic multiple lentigines (DUH1; 127500), previously studied by Pacheco et al. (2002, 2004), Shellman et al. (2015) identified heterozygosity for a c.1556G-A transition in exon 13 of the SASH1 gene, resulting in a ser519-to-asn (S519N) substitution at a highly conserved residue within the SLY domain. The mutation was not found in 18 unaffected family members, 150 ethnically matched controls, or in the UCSC Genome, Ensembl, HapMap, dbSNP, or Japanese SNP databases.
In a 7-year-old Chinese boy (patient 1) with hypo- and hyperpigmented macules over his entire body (DUH1; 127500), Zhang et al. (2016) identified heterozygosity for a c.1537A-C transversion in the SASH1 gene, resulting in a ser513-to-arg (S513R) substitution within the highly conserved SLY domain. The mutation was not found in unaffected family members or in 100 controls.
In a Chinese boy (patient 2) with hypo- and hyperpigmented macules over his entire body (DUH1; 127500), Zhang et al. (2016) identified heterozygosity for a 4-bp duplication (c.1527_1530dupAAGT) in the SASH1 gene. Sequencing confirmed the premature termination codon (Leu511LysfsTer21) resulting from the frameshift. The mutation was not found in unaffected family members or in 100 controls.
In a Chinese mother and son with multiple lentigines (DUH1; 127500), Wang et al. (2017) identified heterozygosity for a c.1519T-G transversion (c.1519T-G, NM_015278.3) in the SASH1 gene, resulting in a ser507-to-ala (S507A) substitution within the SLY domain. The mutation arose de novo in the mother; it was not found in the maternal grandparents or unaffected father, or in 100 controls.
In a proband (proband 2) and all other affected members of a Chinese family with dyschromatosis universalis hereditaria (DUH1; 127500), Zhong et al. (2019) identified heterozygosity for a c.1651T-C transition in the SASH1 gene, resulting in a tyr551-to-his (Y551H) substitution within the SLY domain. The mutation segregated fully with disease in the family.
In a proband (proband 1) and all other affected members of a Chinese family with dyschromatosis universalis hereditaria (DUH1; 127500), Zhong et al. (2019) identified heterozygosity for a c.1784T-C transition in the SASH1 gene, resulting in a met595-to-thr (M595T) substitution within the SH3 domain. The mutation segregated fully with disease in the family.
Courcet, J.-B., Elalaoui, S. C., Duplomb, L., Tajir, M., Riviere, J.-B., Thevenon, J., Gigot, N., Marle, N., Aral, B., Duffourd, Y., Sarasin, A., Naim, V., Courcet-Degrolard, E., Aubriot-Lorton, M.-H., Martin, L., Abrid, J. E., Thauvin, C., Sefiani, A., Vabres, P., Faivre, L. Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma. Europ. J. Hum. Genet. 23: 957-962, 2015. [PubMed: 25315659] [Full Text: https://doi.org/10.1038/ejhg.2014.213]
Dauphinee, S. M., Clayton, A., Hussainkhel, A., Yang, C., Park, Y.-J., Fuller, M. E., Blonder, J., Veenstra, T. D., Karsan, A. SASH1 is a scaffold molecule in endothelial TLR4 signaling. J. Immun. 191: 892-901, 2013. [PubMed: 23776175] [Full Text: https://doi.org/10.4049/jimmunol.1200583]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Pacheco, T. R., Oreskovich, N. M., Bellus, G. A., Talbert, J., Old, W., Fain, P. R. Exclusion of candidate genes and loci for multiple lentigines syndrome. J. Invest. Derm. 119: 535-538, 2002. [PubMed: 12190883] [Full Text: https://doi.org/10.1046/j.1523-1747.2002.18203.x]
Pacheco, T. R., Oreskovich, N. M., Fain, P. Genetic heterogeneity in the multiple lentigines/LEOPARD/Noonan syndromes. Am. J. Med. Genet. 127A: 324-326, 2004. [PubMed: 15150790] [Full Text: https://doi.org/10.1002/ajmg.a.20591]
Shellman, Y. G., Lambert, K. A., Brauweiler, A., Fain, P., Spritz, R. A., Martini, M., Janssen, K.-P., Box, N. F., Terzian, T., Rewers, M., Horvath, A., Stratakis, C. A., Robinson, W. A., Robinson, S. E., Norris, D. A., Artinger, K. B., Pacheco, T. R. SASH1 is involved in an autosomal dominant lentiginous phenotype. J. Invest. Derm. 135: 3192-3194, 2015. [PubMed: 26203640] [Full Text: https://doi.org/10.1038/jid.2015.292]
Wang, J., Zhang, J., Li, X., Wang, Z., Lei, D., Wang, G., Li, J., Zhang, S., Li, Z., Li, M. A novel de novo mutation of the SASH1 gene in a Chinese family with multiple lentigines. Acta Derm. Venereol. 97: 530-531, 2017. [PubMed: 27840890] [Full Text: https://doi.org/10.2340/00015555-2575]
Zeller, C., Hinzmann, B., Seitz, S., Prokoph, H., Burkhard-Goettges, E., Fischer, J., Jandrig, B., Schwartz, L.-E., Rosenthal, A., Scherneck, S. SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer. Oncogene 22: 2972-2983, 2003. [PubMed: 12771949] [Full Text: https://doi.org/10.1038/sj.onc.1206474]
Zhang, J., Cheng, R., Liang, J., Ni, C., Li, M., Yao, Z. Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination. Clin. Genet. 90: 372-377, 2016. [PubMed: 27659786] [Full Text: https://doi.org/10.1111/cge.12728]
Zhong, W.-L., Wang, H.-J., Lin, Z.-M., Yang, Y. Novel mutations in SASH1 associated with dyschromatosis universalis hereditaria. Indian J. Derm. Venereol. Leprol. 85: 440, 2019. Note: Electronic Article. [PubMed: 29956681] [Full Text: https://doi.org/10.4103/ijdvl.IJDVL_360_17]
Zhou, D., Wei, Z., Deng, S., Wang, T., Zai, M., Wang, H., Guo, L., Zhang, J., Zhong, H., He, L., Xing, Q. SASH1 regulates melanocyte transepithelial migration through a novel G-alpha-S--SASH1--IQGAP1--E-cadherin dependent pathway. Cell. Signal. 25: 1526-1538, 2013. [PubMed: 23333244] [Full Text: https://doi.org/10.1016/j.cellsig.2012.12.025]
Zhou, D., Wei, Z., Kuang, Z., Luo, H., Ma, J., Zeng, X., Wang, K., Liu, B., Gong, F., Wang, J., Lei, S., Wang, D., Zeng, J., Wang, T., He, Y., Yuan, Y., Dai, H., He, L., Xing, Q. A novel P53/POMC/G-alpha-S/SASH1 autoregulatory feedback loop activates mutated SASH1 to cause pathologic hyperpigmentation. J. Cell. Molec. Med. 21: 802-815, 2017. [PubMed: 27885802] [Full Text: https://doi.org/10.1111/jcmm.13022]