HGNC Approved Gene Symbol: SACS
SNOMEDCT: 702445005;
Cytogenetic location: 13q12.12 Genomic coordinates (GRCh38) : 13:23,328,830-23,433,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.12 | Spastic ataxia, Charlevoix-Saguenay type | 270550 | Autosomal recessive | 3 |
The SACS gene encodes sacsin, a protein believed to integrate the ubiquitin-proteasome system and Hsp70 chaperone machinery and implicated in the processing of ataxin-1 (ATXN1; 601556) (Parfitt et al., 2009).
Engert et al. (2000) reported the cloning of the SACS gene, which encodes the protein sacsin. The open reading frame is conserved in human and mouse. Sequence analysis of the 3,829-amino acid SACS protein predicted 2 leucine zippers, 3 coiled-coils, and 7 nuclear localization signals. The C-terminal portion of the protein contains a hydrophilic domain and a DnaJ motif (see 604189). The putative protein contains 3 large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana open reading frame. The presence of heat-shock domains suggested a function for sacsin in chaperone-mediated protein folding. Northern blot analysis detected SACS expression as a 12.8-kb transcript in fibroblasts, brain, skeletal muscle, and at low levels in pancreas. In situ hybridization to human, monkey, and rat brain tissue showed intense labeling in all areas of the central nervous system.
With the finding of 8 additional exons, the SACS gene is predicted to encode a 4,579-amino acid protein (Ouyang et al., 2006). Parfitt et al. (2009) identified an ubiquitin-like (UBL) domain in the N terminus of sacsin that interacted with the proteasome.
Romano et al. (2013) characterized the 3 sacsin repeating region (SRR) supradomains and determined that they are much larger (1,100 residues or more) than previously reported. These regions are organized into discrete subrepeats. The large repeated regions were termed 'Sacsin Internal RePeaTs' (SIRPT1, SIRPT2, and SIRPT3), and the subrepeats sr1, sr2, sr3, and srX. Comparative analysis of vertebrate sacsins showed that these regions are highly conserved among vertebrates. Fine positional mapping of a set of human SACS mutations revealed that sr1, sr2, sr3, and srX are functional. In addition, the position of the pathogenic mutations in sr1, sr2, sr3, and srX appeared to be related to the severity of the clinical phenotype, as assessed by defining a severity scoring system. These results suggested that the relative position of mutations in subrepeats will variably influence sacsin dysfunction.
Engert et al. (2000) found that the 11,487-bp open reading frame of SACS is encoded by a single gigantic exon spanning 12,794 bp. This exon was the largest to be identified in any vertebrate organism. The largest exons previously reported were those of the X inactivation-specific transcript (XIST; 314670), which does not encode a protein, 11,363 bp; and an exon of the mucin gene (MUC5B; 600770), measuring 10,713 bp.
Eight novel exons located upstream of the gigantic exon have been identified, bringing the total number of exons in the SACS gene to 9. The gigantic exon is referred to as exon 9 (Ouyang et al., 2006).
Baets et al. (2010) stated that the SACS gene maps to chromosome 13q12.12.
The mouse Sacs gene maps to chromosome 1, near D1Mit373 (Engert et al., 2000).
Parfitt et al. (2009) determined that sacsin is most highly expressed in large neurons, including cerebellar Purkinje cells. Sacsin showed predominantly cytoplasmic localization with a mitochondrial component in neuroblastoma cells. The presence of both UBL and J-domains in sacsin suggested that it may integrate the ubiquitin-proteasome system and Hsp70 (HSPA1A; 140550) function to a specific cellular role. Knockdown of SACS by siRNA did not affect viability of cells transfected with wildtype ataxin-1(30Q) (601556) but enhanced the toxicity of ataxin-1(82Q), suggesting that sacsin is protective against CAG-mutant ataxin-1. Parfitt et al. (2009) concluded that sacsin is an ataxia protein and a regulator of the Hsp70 chaperone machinery that is implicated in the processing of other ataxia-linked proteins.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS; 270550) is an early-onset neurodegenerative disease with high prevalence (carrier frequency, 1 in 22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec, Canada. Engert et al. (2000) identified 2 SACS mutations in ARSACS families that lead to protein truncation (604490.0001-604490.0002). The 2 different mutations corresponded to the 2 different haplotypes previously identified by Engert et al. (1999).
In 4 Tunisian families with autosomal recessive ataxia phenotypically similar to ARSACS, 3 of which were consanguineous, El Euch-Fayache et al. (2003) identified 4 mutations in the SACS gene (604490.0003-604490.0006).
Criscuolo et al. (2004) and Ogawa et al. (2004) identified mutations in the SACS gene in ARSACS patients from southern Italy and Japan, respectively (see 604490.0007 and 604490.0008).
Richter et al. (2004) identified 4 different homozygous mutations in the SACS gene in 4 Turkish families with ARSACS. A founder mutation was not identified.
In a Japanese woman with ARSACS, Ouyang et al. (2006) identified compound heterozygosity for 2 mutations in exon 7 of the SACS gene (604490.0010; 604490.0011). The patient had classic clinical features of early-onset spastic ataxia but no retinal hypermyelination. Ouyang et al. (2006) emphasized the need to examine all SACS exons, not only the gigantic exon 9, in patients with a clinical phenotype compatible with ARSACS.
Baets et al. (2010) identified homozygous or compound heterozygous mutations in the SACS gene in 11 (12.9%) of 85 index patients with phenotypes suggestive of ARSACS. Eighteen different mutations were identified, including 11 missense, 5 frameshift, 1 nonsense, and 1 in-frame deletion. A founder allele was identified in 4 unrelated Belgian families. Five patients had onset after age 20 years, including 1 with onset at age 40. In addition, some patients presented with predominant features of peripheral neuropathy, although most eventually developed the classic signs of the disorder, namely cerebellar ataxia and pyramidal signs. Only 1 of 17 patients had mild mental retardation, and 2 had reduced IQ. There were no clear genotype/phenotype correlations.
A recessive mouse mutation, 'tumbler' (tb), was previously mapped to chromosome 1 by linkage (Dickie, 1965). Tumbler mice had ataxia, causing them to walk in a crab-like fashion and fall over when trying to move forward. The tb mouse line had died out, but Engert et al. (2000) speculated that it harbored a mutation in Sacs.
Among patients with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), 2 ancestral haplotypes had been identified (Engert et al., 1999). Engert et al. (2000) sequenced the DNA from ARSACS patients and controls and found a single-base deletion of a T at position 6594 on all copies of the major ancestral haplotype examined. This mutation resulted in a frameshift and introduction of a stop codon.
Criscuolo et al. (2004) stated that the 6594delT mutation accounts for approximately 94% of the disease alleles among individuals in the French Canadian population with ARSACS.
Engert et al. (2000) found a C-to-T transition at nucleotide 5254 of the SACS gene in 6 patients with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550) who carried the minor haplotype. The 5254C-T mutation, which predicts the substitution of a stop codon for arginine, was found in compound heterozygous state with the 6594delT mutation (604490.0001).
In a Tunisian family with autosomal recessive ataxia similar to spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), El Euch-Fayache et al. (2003) identified a 10046G-C transversion in the SACS gene, resulting in an ala3324-to-pro (A3324P) substitution. The mutation was not identified in 100 control chromosomes.
In a Tunisian family with autosomal recessive ataxia similar to spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), El Euch-Fayache et al. (2003) identified a 1-bp deletion (1411delT) in the SACS gene, resulting in a premature stop codon and a truncated peptide of 456 amino acids. The mutation was not identified in 100 control chromosomes.
In a Tunisian family with autosomal recessive ataxia similar to spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), El Euch-Fayache et al. (2003) identified a 1-bp insertion (1155insA) in the SACS gene, producing a truncated peptide of 360 amino acids. The mutation was not identified in 100 control chromosomes.
In a Tunisian family with autosomal recessive ataxia similar to spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), El Euch-Fayache et al. (2003) identified a 3662T-C transition in the SACS gene, resulting in a trp1196-to-arg (W1196R) substitution. The mutation was not identified in 100 control chromosomes.
In 2 sisters with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), born of consanguineous parents in southern Italy, Criscuolo et al. (2004) identified homozygosity for a 1-bp insertion, 1859insC, in the SACS gene, resulting in a frameshift and a premature stop codon at position 599. The resulting protein lacked 3,230 amino acids. Both sisters showed a clinical phenotype similar to other reported patients with ARSACS; one of the sisters also had mental retardation and hypoacusis.
In a Japanese sister and brother with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), Ogawa et al. (2004) identified a homozygous 7492T-C transition in the SACS gene, resulting in a trp2498-to-arg (W2498R) substitution in a conserved residue. The mutation was not found in 200 Japanese controls.
In 2 Japanese brothers, born of consanguineous parents, with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), Shimazaki et al. (2005) identified a homozygous 987T-C transition in the SACS gene, resulting in a phe304-to-ser (F304S) substitution. Each parent was heterozygous for the mutation, which was not identified in 208 control chromosomes. The phenotype was unique in that neither patient had spasticity or hyperreflexia, although both had extensor plantar responses, indicating pyramidal tract dysfunction.
In a Japanese woman with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550), Ouyang et al. (2006) identified compound heterozygosity for 2 mutations in exon 7 of the SACS gene: a 10-bp deletion (32627delACACTGTTAC) and a 1-bp deletion (31760delT; 604490.0011). Both mutations were predicted to result in premature termination of the protein; each unaffected parent was heterozygous for 1 of the mutations. The patient had classic clinical features of early-onset spastic ataxia but no retinal hypermyelination.
For discussion of the 1-bp deletion in the SACS gene (31760delT) that was found in compound heterozygous state in a patient with spastic ataxia of the Charlevoix-Saguenay type (ARSACS; 270550) by Ouyang et al. (2006), see 604490.0010.
Baets, J., Deconinck, T., Smets, K., Goossens, D., Van den Bergh, P., Dahan, K., Schmedding, E., Santens, P., Rasic, V. M., Van Damme, P., Robberecht, W., De Meirleir, L., Michielsens, B., Del-Favero, J., Jordanova, A., De Jonghe, P. Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology 75: 1181-1188, 2010. [PubMed: 20876471] [Full Text: https://doi.org/10.1212/WNL.0b013e3181f4d86c]
Criscuolo, C., Banfi, S., Orio, M., Gasparini, P., Monticelli, A., Scarano, V., Santorelli, F. M., Perretti, A., Santoro, L., De Michele, G., Filla, A. A novel mutation in SACS gene in a family from southern Italy. Neurology 62: 100-102, 2004. [PubMed: 14718706] [Full Text: https://doi.org/10.1212/wnl.62.1.100]
Dickie, M. M. Tumbler, tb. Mouse News Lett. 32: 45 only, 1965.
El Euch-Fayache, G., Lalani, I., Amouri, R., Turki, I., Ouahchi, K., Hung, W.-Y., Belal, S., Siddique, T., Hentati, F. Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch. Neurol. 60: 982-988, 2003. [PubMed: 12873855] [Full Text: https://doi.org/10.1001/archneur.60.7.982]
Engert, J. C., Berube, P., Mercier, J., Dore, C., Lepage, P., Ge, B., Bouchard, J.-P., Mathieu, J., Melancon, S. B., Schalling, M., Lander, E. S., Morgan, K., Hudson, T. J., Richter, A. ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nature Genet. 24: 120-125, 2000. [PubMed: 10655055] [Full Text: https://doi.org/10.1038/72769]
Engert, J. C., Dore, C., Mercier, J., Ge, B., Betard, C., Rioux, J. D., Owen, C., Berube, P., Devon, K., Birren, B., Melancon, S. B., Morgan, K., Hudson, T. J., Richter, A. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): high-resolution physical and transcript map of the candidate region in chromosome region 13q11. Genomics 62: 156-164, 1999. [PubMed: 10610707] [Full Text: https://doi.org/10.1006/geno.1999.6003]
Ogawa, T., Takiyama, Y., Sakoe, K., Mori, K., Namekawa, M., Shimazaki, H., Nakano, I., Nishizawa, M. Identification of a SACS gene missense mutation in ARSACS. Neurology 62: 107-109, 2004. [PubMed: 14718708] [Full Text: https://doi.org/10.1212/01.wnl.0000099371.14478.73]
Ouyang, Y., Takiyama, Y., Sakoe, K., Shimazaki, H., Ogawa, T., Nagano, S., Yamamoto, Y., Nakano, I. Sacsin-related ataxia (ARSACS): expanding the genotype upstream from the gigantic exon. Neurology 66: 1103-1104, 2006. [PubMed: 16606928] [Full Text: https://doi.org/10.1212/01.wnl.0000204300.94261.ea]
Parfitt, D. A., Michael, G. J., Vermeulen, E. G. M., Prodromou, N. V., Webb, T. R., Gallo, J.-M., Cheetham, M. E., Nicoll, W. S., Blatch, G. L., Chapple, J. P. The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum. Molec. Genet. 18: 1556-1565, 2009. [PubMed: 19208651] [Full Text: https://doi.org/10.1093/hmg/ddp067]
Richter, A. M., Ozgul, R. K., Poisson, V. C., Topaloglu, H. Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey. Neurogenetics 5: 165-170, 2004. [PubMed: 15156359] [Full Text: https://doi.org/10.1007/s10048-004-0179-y]
Romano, A., Tessa, A., Barca, A., Fattori, F., de Leva, M. F., Terracciano, A., Storelli, C., Santorelli, F. M., Verri, T. Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture. Hum. Mutat. 34: 525-537, 2013. [PubMed: 23280630] [Full Text: https://doi.org/10.1002/humu.22269]
Shimazaki, H., Takiyama, Y., Sakoe, K., Ando, Y., Nakano, I. A phenotype without spasticity in sacsin-related ataxia. Neurology 64: 2129-2131, 2005. [PubMed: 15985586] [Full Text: https://doi.org/10.1212/01.WNL.0000166031.91514.B3]