HGNC Approved Gene Symbol: SETX
SNOMEDCT: 725408001, 784341001;
Cytogenetic location: 9q34.13 Genomic coordinates (GRCh38) : 9:132,261,356-132,356,744 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.13 | Amyotrophic lateral sclerosis 4, juvenile | 602433 | Autosomal dominant | 3 |
| Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 | 606002 | Autosomal recessive | 3 |
SETX is an ATP-dependent helicase that is required for unwinding and resolution of RNA:DNA hybrids (R-loops) formed during transcription (Kannan et al., 2022).
By a positional cloning strategy, Moreira et al. (2004) identified the SETX gene within the interval on chromosome 9q34 associated with autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN2; 606002), earlier referred to as ataxia-oculomotor apraxia-2 (AOA2). The predicted 2,677-amino acid protein contains at its C terminus a classic 7-motif domain found in the superfamily 1 of helicases. Moreira et al. (2004) named the gene 'senataxin' for its extensive homology to fungal Sen1p proteins. In Saccharomyces cerevisiae, Sen1p is involved in splicing and termination of tRNA, small nuclear RNA, and small nucleolar RNA, and has RNA helicase activity encoded by its C-terminal domain. Senataxin shares significant similarity with another helicase, IGHMBP2 (600502), which is mutant in spinal muscular atrophy with respiratory distress-1 (SMARD1, DSMA1; 604320), a disorder of motor neurons, and in mouse neuromuscular degeneration (Cox et al., 1998). Moreira et al. (2004) suggested that senataxin may have both RNA and DNA helicase activities and that senataxin acts in the DNA repair pathway, like several other proteins defective in autosomal recessive cerebellar ataxias.
Chen et al. (2004) determined that the SETX gene encodes a 302.8-kD protein. Northern blot analysis identified 2 prominent transcripts of 11.5 and 9.0 kb in all tissues examined, including brain and spinal cord. SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 (601430) and IGHMBP2 (600502), 2 genes that encode proteins known to have roles in RNA processing.
Moreira et al. (2004) determined that the SETX gene contains 24 exons.
Suraweera et al. (2009) identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II (see POLR2A, 180660). Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin-deficient cells, accompanied by decreased transcription of these genes, thus suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin, in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 (PABP1; 604679) and 2 (PABP2; 602279). Splicing efficiency of specific mRNAs and alternate splice site selection of both endogenous genes and artificial minigenes were altered in senataxin-depleted cells. Suraweera et al. (2009) suggested that senataxin, similar to its yeast homolog Sen1p, may play a role in coordinating transcriptional events, in addition to its role in DNA repair.
Zhao et al. (2016) showed that a carboxy-terminal domain (CTD) arginine (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires PRMT5 (604045) and recruits the Tudor domain of SMN (600354). SMN interacts with senataxin. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, Zhao et al. (2016) proposed that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway.
By immunoprecipitation analysis in HeLa cells, Kannan et al. (2022) showed that ZPR1 (603901) interacted with SETX. ZPR1 also bound to R-loops to facilitate SETX recruitment for the formation of an R-loop resolution complex (RLRC) during transcription. ZPR1 colocalized with SETX in nuclear bodies in HeLa cells, and knockdown of ZPR1 resulted in downregulation of SETX and accumulation of R-loops, indicating that ZPR1 was critical for R-loop resolution. Moreover, knockdown of SETX caused disruption of ZPR1-positive subnuclear bodies, gems, and Cajal bodies and accumulation of R-loops, indicating a functional contribution of SETX in ZPR1-dependent resolution of R-loops. Analysis with fibroblasts from patients with spinal muscular atrophy (SMA; 253300) revealed that chronic low levels of ZPR1 caused defects in RLRC assembly, which resulted in inefficient R-loop resolution and accumulation of pathogenic R-loops and DNA damage, leading to genomic instability and neurodegeneration. In contrast, ZPR1 overexpression rescued defective RLRC assembly and prevented pathogenic R-loop accumulation in SMA patient cells in vitro, and Zpr1 overexpression rescued DNA damage associated with R-loop accumulation and prevented degeneration of motor neurons in SMA mice in vivo. Further analysis of SETX mutations in ALS4 (602433) patient cells (see MOLECULAR GENETICS) confirmed that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity.
The SETX gene lies within the 9q34 region linked to ataxia-oculomotor apraxia-2 (Moreira et al., 2004).
Autosomal Recessive Spinocerebellar Ataxia with Axonal Neuropathy
Moreira et al. (2004) sequenced exons 1 through 18 of the SETX gene and flanking intronic sequences in families with ataxia linked to the 9q34 region and in additional individuals with either ataxia-oculomotor apraxia or ataxia with elevated levels of alpha-fetoprotein (SCAN2; 606002) and found 15 different disease-associated mutations in 15 families.
In affected members of 10 French Canadian families with ataxia, distal amyotrophy, and peripheral neuropathy, Duquette et al. (2005) identified mutations in the SETX gene. A founder mutation, leu1976 to arg (L1976R; 606465.0009), was identified in all families.
Fogel and Perlman (2006) identified 6 SETX mutations, including 5 novel mutations (see, e.g., 606465.0012), in 3 unrelated patients with ataxia-oculomotor apraxia-2. Three of the mutations were in the DNA/RNA helicase functional domain, illustrating the importance of this region to the pathogenesis of the disorder.
Arning et al. (2008) reported a patient with ataxia-oculomotor apraxia-2 who was found to be compound heterozygous for a point mutation in the SETX gene and a large out-of-frame tandem duplication encompassing exons 7 through 10 of the SETX gene. The duplication occurred by unequal homologous recombination between AluY sequences. The authors suggested that gross deletions or duplications in the SETX gene may be an underestimated cause of the disorder.
Airoldi et al. (2010) identified a homozygous in-frame deletion of leu144 in the SETX gene (L144del; 608465.0014) in 2 sisters with ataxia-oculumotor apraxia-2 The deletion affected an N-terminal region predicted to act as a protein-protein interaction domain. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. Airoldi et al. (2010) postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage.
By gene expression profiling of fibroblasts derived from a patient with ataxia-oculomotor apraxia-2 and an unaffected heterozygous carrier, Fogel et al. (2014) identified a core set of genes with altered expression levels in the patient, including genes involved in neurogenesis, cell proliferation, and synaptic transmission. Overexpression of an AOA2-associated mutation (L1976R; 608465.0009) and an ALS4-associated mutation (R2136H; 608465.0008) resulted in differential gene expression patterns, suggesting that disease-specific mutations cause differential transcriptional changes within cells. However, there were some modules of overlap involving aspects of RNA processing, DNA maintenance, and transcription. The findings identified novel genes and cellular pathways related to senataxin function.
Juvenile Amyotrophic Lateral Sclerosis 4
Juvenile amyotrophic lateral sclerosis (ALS4; 602433) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Chen et al. (2004) tested 19 genes within the ALS4 interval on 9q34 and detected 3 missense mutations (608465.0006-608465.0008) in the SETX gene. The observations of ALS4 suggested that mutations in SETX may cause neuronal degeneration through dysfunction of helicase activity or other steps in RNA processing.
Kannan et al. (2022) found that the heterozygous L389S mutation in SETX disrupted interaction of SETX with ZPR1, leading to mislocalization of SETX and ZPR1 in ALS4 patient cells. ALS4 patient cells displayed reduced R-loop levels, because the SETX mutation altered the dynamic equilibrium of SETX dimers and caused disruption of SETX-ZPR1 complexes, likely resulting in partial impairment of the molecular brake leading to faster resolution (i.e., gain of function) and fewer R-loops in ALS4. Moreover, analysis with ALS4 patient fibroblasts revealed that SETX mutations decreased its in vivo association with R-loops. Modulation of ZPR1 levels regulated R-loop accumulation and rescued the pathogenic R-loop phenotype, suggesting that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity and that disruption of ZPR1-SETX complexes is the molecular basis for ALS4 pathogenesis.
In 3 seemingly unrelated families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) found homozygosity for a 4087C-T transition in the SETX gene, resulting in an arg1363-to-ter (R1363X) premature termination of the protein product. The 3 families originated from Portugal, Cabo Verde (once a Portuguese colony), and Spain, suggesting an Iberian founder event, although recurrent C-T changes on this CpG dinucleotide could not be formally excluded.
In an Algerian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) found a homozygous 2602C-T transition in the SETX gene, which resulted in a gln868-to-stop (Q868X) protein truncation.
In a Japanese family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SETX; 606002), Moreira et al. (2004) found homozygosity for a 6638C-T transition in the SETX gene, resulting in a pro2213-to-leu (P2213L) amino acid substitution.
In a French family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) identified compound heterozygous mutations in the SETX gene: a 5-bp deletion in exon 8, 2966_2970delGGAAA, causing a frameshift after Q988, and a 944C-T transition, resulting in an arg332-to-trp (R332W; 608465.0005) substitution.
For discussion of the arg332-to-trp (R332W) mutation in the SETX gene that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002) by Moreira et al. (2004), see 608465.0004.
In the large Maryland family with an autosomal dominant form of juvenile amyotrophic lateral sclerosis described by Chance et al. (1998) and others (ALS4; 602433), Chen et al. (2004) found heterozygosity for a leu389-to-ser (L389S) substitution in senataxin that arose from a 1166T-C transition in the SETX gene. At the time of the report of Chen et al. (2004), 55 members of this family were affected. Mean age at onset was 17 years. Approximately 10% of affected persons had minimal sensory impairment, usually limited to a slight elevation of vibratory threshold in middle-aged or elderly patients. Otherwise, affected persons had no overt clinical signs of sensory nerve impairment.
In a family classified as having autosomal dominant juvenile amyotrophic lateral sclerosis-4 (ALS4; 602433), Chen et al. (2004) found a heterozygous 8C-T transition in exon 3 of the SETX gene (exons 1 and 2 are noncoding) leading to a thr3-to-ile (T3I) substitution. The mean age of onset was 8 years.
In a Belgian family, Chen et al. (2004) found that autosomal dominant amyotrophic lateral sclerosis-4 (ALS4; 602433) was associated with an arg2136-to-his (R2136H) substitution in the SETX gene.
In affected members of 7 unrelated French Canadian families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Duquette et al. (2005) identified a homozygous 5927T-G transversion in the SETX gene, resulting in a leu1976-to-arg (L1976R) substitution in the helicase domain of the protein. Affected members from 3 additional families had the L1986R mutation in compound heterozygosity with another disease-causing SETX mutation. The carrier rate for the L1986R mutation was estimated at 3.5% for Quebecois of Anglo-Norman descent and 2.1% in the French Canadian population of Gaspesie. All patients had a similar phenotype characterized by progressive ataxia, distal amyotrophy, and sensory impairment, but without oculomotor apraxia as strictly defined.
In a patient with SCAN2, Fogel and Perlman (2006) identified compound heterozygosity for 2 mutations in the SETX gene: L1976R and L1977F (608465.0012).
In an African American mother and daughter with a restricted form of autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Bassuk et al. (2007) identified 2 mutations in cis in the SETX gene: a 1807A-G transition, resulting in an asn603-to-asp (N603D) substitution, and a 1957C-A transversion, resulting in a gln653-to-lys (Q653K) substitution. The mutations occurred in a region adjacent to a putative N-terminal protein interaction domain. Detailed analysis confirmed that the 2 mutations were on the same allele and were part of the same haplotype. Although both mother and daughter had frequent falls, oculomotor deficits, and tremor, neither had peripheral neuropathy or 'head thrusting' associated with horizontal gaze, both of which are classic findings in SCAN2. Bassuk et al. (2007) postulated that the 2 mutations acted synergistically, leading to a dominant-negative mutant protein with partial function and an incomplete phenotype.
In 2 Japanese sibs, born of consanguineous parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Asaka et al. (2006) identified homozygosity for 2 mutations in the SETX gene: met274-to-ile (M274I) and arg1294-to-cys (R1294C). Both had late-teenage onset of severe cerebellar ataxia with rapid progression, peripheral neuropathy, increased serum AFP, and distal muscle atrophy. Oculomotor apraxia was unclear. The mutations affected conserved residues and were not identified in 400 control chromosomes. Three unaffected sibs were heterozygous for the 2 mutations, and all had normal serum AFP.
In a 22-year-old man with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Fogel and Perlman (2006) identified compound heterozygosity for 2 mutations in the SETX gene: leu1977-to-phe (L1977F) and L1976R (608465.0009). Both mutations lie in the conserved DNA/RNA helicase domain of the protein. The patient had onset of progressive gait and limb ataxia at age 16. Other features included oculomotor apraxia, dysarthria, axonal peripheral sensory neuropathy, and tremor. Each unaffected parent was heterozygous for 1 of the mutations.
In 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Anheim et al. (2008) identified a homozygous 1027G-T transversion in exon 7 of the SETX gene, resulting in a glu343-to-ter (E343X) substitution. All had teenage onset of progressive cerebellar ataxia and areflexia. The unaffected parents were heterozygous for the mutation.
In 2 sisters with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), who were born of consanguineous parents, Airoldi et al. (2010) identified a homozygous 3-bp deletion (340_342delCTT) in the SETX gene, resulting in an in-frame deletion of leu144 (L144del) in an N-terminal region predicted to act as a protein-protein interaction domain. The deletion was outside of the putative helicase region. Both sisters had onset in their twenties of progressive cerebellar ataxia resulting in wheelchair-dependence in their forties. Other features included tremor, dysarthria, ocular motor deficits, and severe distal muscular atrophy. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. Airoldi et al. (2010) postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage.
Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T. Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin. Neurogenetics 11: 91-100, 2010. [PubMed: 19593598] [Full Text: https://doi.org/10.1007/s10048-009-0206-0]
Anheim, M., Fleury, M.-C., Franques, J., Moreira, M.-C., Delaunoy, J.-P., Stoppa-Lyonnet, D., Koenig, M., Tranchant, C. Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families. Arch. Neurol. 65: 958-962, 2008. [PubMed: 18625865] [Full Text: https://doi.org/10.1001/archneur.65.7.958]
Arning, L., Schols, L., Cin, H., Souquet, M., Epplen, J. T., Timmann, D. Identification and characterisation of a large senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2). Neurogenetics 9: 295-299, 2008. [PubMed: 18663494] [Full Text: https://doi.org/10.1007/s10048-008-0139-z]
Asaka, T., Yokoji, H., Ito, J., Yamaguchi, K., Matsushima, A. Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. Neurology 66: 1580-1581, 2006. [PubMed: 16717225] [Full Text: https://doi.org/10.1212/01.wnl.0000216135.59699.9b]
Bassuk, A. G., Chen, Y. Z., Batish, S. D., Nagan, N., Opal, P., Chance, P. F., Bennett, C. L. In cis autosomal dominant mutation of senataxin associated with tremor/ataxia syndrome. Neurogenetics 8: 45-49, 2007. [PubMed: 17096168] [Full Text: https://doi.org/10.1007/s10048-006-0067-8]
Chance, P. F., Rabin, B. A., Ryan, S. G., Ding, Y., Scavina, M., Crain, B., Griffin, J. W., Cornblath, D. R. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am. J. Hum. Genet. 62: 633-640, 1998. [PubMed: 9497266] [Full Text: https://doi.org/10.1086/301769]
Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74: 1128-1135, 2004. [PubMed: 15106121] [Full Text: https://doi.org/10.1086/421054]
Cox, G. A., Mahaffey, C. L., Frankel, W. N. Identification of mouse neuromuscular degeneration gene and mapping of a second site suppressor allele. Neuron 21: 1327-1337, 1998. [PubMed: 9883726] [Full Text: https://doi.org/10.1016/s0896-6273(00)80652-2]
Duquette, A., Roddier, K., McNabb-Baltar, J., Gosselin, I., St-Denis, A., Dicaire, M.-J., Loisel, L., Labuda, D., Marchand, L., Mathieu, J., Bouchard, J.-P., Brais, B. Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann. Neurol. 57: 408-414, 2005. [PubMed: 15732101] [Full Text: https://doi.org/10.1002/ana.20408]
Fogel, B. L., Cho, E., Wahnich, A., Gao, F., Becherel, O. J., Wang, X., Fike, F., Chen, L., Criscuolo, C., De Michele, G., Filla, A., Collins, A., Hahn, A. F., Gatti, R. A., Konopka, G., Perlman, S., Lavin, M. F., Geschwind, D. H., Coppola, G. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. Hum. Molec. Genet. 23: 4758-4769, 2014. [PubMed: 24760770] [Full Text: https://doi.org/10.1093/hmg/ddu190]
Fogel, B. L., Perlman, S. Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2. Neurology 67: 2083-2084, 2006. [PubMed: 17159128] [Full Text: https://doi.org/10.1212/01.wnl.0000247661.19601.28]
Kannan, A., Cuartas, J., Gangwani, P., Branzei, D., Gangwani, L. Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4. Brain 145: 3072-3094, 2022. [PubMed: 35045161] [Full Text: https://doi.org/10.1093/brain/awab464]
Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nature Genet. 36: 225-227, 2004. [PubMed: 14770181] [Full Text: https://doi.org/10.1038/ng1303]
Suraweera, A., Lim, Y., Woods, R., Birrell, G. W., Nasim, T., Becherel, O. J., Lavin, M. F. Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation. Hum. Molec. Genet. 18: 3384-3396, 2009. [PubMed: 19515850] [Full Text: https://doi.org/10.1093/hmg/ddp278]
Zhao, D. Y., Gish, G., Braunschweig, U., Li, Y., Ni, Z., Schmitges, F. W., Zhong, G., Liu, K., Li, W., Moffat, J., Vedadi, M., Min, J., Pawson, T. J., Blencowe, B. J., Greenblatt, J. F. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529: 48-53, 2016. [PubMed: 26700805] [Full Text: https://doi.org/10.1038/nature16469]