Sacsin Explained

Sacsin also known as DnaJ homolog subfamily C member 29 (DNAJC29) is a protein that in humans is encoded by the SACS gene.^{[1] [2]} Sacsin is a Hsp70 co-chaperone.^[3]

Function

This gene consists of nine exons including a gigantic exon spanning more than 12.8k bp. It encodes the sacsin protein, which includes a UBQ region at the N-terminus, a HEPN domain at the C-terminus and a DnaJ region upstream of the HEPN domain. This modular protein is essential for normal mitochondrial network organization.^[4] The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy.^[2]

Clinical significance

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a very rare neurodegenerative genetic disorder that results from mutations in the gene that produces Sacsin. Afflicted persons suffer from loss of balance, loss of muscle control and spasticity.^[5]

Further reading

• 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 Research . 5 . 5 . 277–86 . October 1998 . 9872452 . 10.1093/dnares/5.5.277 . free .
• Engert JC, Bérubé P, Mercier J, Doré C, Lepage P, Ge B, Bouchard JP, Mathieu J, Melançon SB, Schalling M, Lander ES, Morgan K, Hudson TJ, Richter A . ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF . Nature Genetics . 24 . 2 . 120–5 . February 2000 . 10655055 . 10.1038/72769 . 19667726 .
• Mercier J, Prévost C, Engert JC, Bouchard JP, Mathieu J, Richter A . Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay . Genetic Testing . 5 . 3 . 255–9 . 2001 . 11788093 . 10.1089/10906570152742326 .
• Criscuolo C, Banfi S, Orio M, Gasparini P, Monticelli A, Scarano V, Santorelli FM, Perretti A, Santoro L, De Michele G, Filla A . A novel mutation in SACS gene in a family from southern Italy . Neurology . 62 . 1 . 100–2 . January 2004 . 14718706 . 10.1212/wnl.62.1.100 . 42697050 .
• Grieco GS, Malandrini A, Comanducci G, Leuzzi V, Valoppi M, Tessa A, Palmeri S, Benedetti L, Pierallini A, Gambelli S, Federico A, Pierelli F, Bertini E, Casali C, Santorelli FM . Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type . Neurology . 62 . 1 . 103–6 . January 2004 . 14718707 . 10.1212/01.wnl.0000104491.66816.77 . 8767156 .
• 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 . 1 . 107–9 . January 2004 . 14718708 . 10.1212/01.wnl.0000099371.14478.73 . 46133910 .
• Richter AM, Ozgul RK, Poisson VC, Topaloglu H . Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey . Neurogenetics . 5 . 3 . 165–70 . September 2004 . 15156359 . 10.1007/s10048-004-0179-y . 13187102 .
• Shimazaki H, Takiyama Y, Sakoe K, Ando Y, Nakano I . A phenotype without spasticity in sacsin-related ataxia . Neurology . 64 . 12 . 2129–31 . June 2005 . 15985586 . 10.1212/01.WNL.0000166031.91514.B3 . 22975541 .
• Yamamoto Y, Hiraoka K, Araki M, Nagano S, Shimazaki H, Takiyama Y, Sakoda S . Novel compound heterozygous mutations in sacsin-related ataxia . Journal of the Neurological Sciences . 239 . 1 . 101–4 . December 2005 . 16198375 . 10.1016/j.jns.2005.08.005 . 22286305 .
• 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 . 7 . 1103–4 . April 2006 . 16606928 . 10.1212/01.wnl.0000204300.94261.ea . 19513985 .
• Takado Y, Hara K, Shimohata T, Tokiguchi S, Onodera O, Nishizawa M . New mutation in the non-gigantic exon of SACS in Japanese siblings . Movement Disorders . 22 . 5 . 748–9 . April 2007 . 17290461 . 10.1002/mds.21365 . 23132322 .

External links

• GeneReviews/NCBI/NIH/UW entry on ARSACS - Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay
• OMIM entries on ARSACS - Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Notes and References

1. Engert JC, Doré C, Mercier J, Ge B, Bétard C, Rioux JD, Owen C, Bérubé P, Devon K, Birren B, Melançon SB, Morgan K, Hudson TJ, 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 . 2 . 156–64 . December 1999 . 10610707 . 10.1006/geno.1999.6003 .
2. Web site: Entrez Gene: SACS spastic ataxia of Charlevoix-Saguenay (sacsin).
3. Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM, Cheetham ME, Nicoll WS, Blatch GL, Chapple JP . The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1 . Human Molecular Genetics . 18 . 9 . 1556–65 . May 2009 . 19208651 . 2667285 . 10.1093/hmg/ddp067 .
4. Bradshaw TY, Romano LE, Duncan EJ, Nethisinghe S, Abeti R, Michael GJ, Giunti P, Vermeer S, Chapple JP . A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay . Human Molecular Genetics . 3232–3244 . June 2016 . 27288452 . 10.1093/hmg/ddw173 . 25 . 15 . 5179924.
5. Web site: ARSACS. Genetics Home Reference. 19 January 2017. en.