Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration
Abstract
:1. Introduction: Sacsin (SACS) Gene and ARSACS
2. Sacsin Functions and Cell/Animal Models of ARSACS
3. Sacsin Protein Domains
4. SACS Genetics and Mutations
Mutation | Exon | Domain | AOO | Clinical Symptoms | Neurological Changes | Population (Ethnicity) | Refs. |
---|---|---|---|---|---|---|---|
c.6594delT (I2949Ffs*4,) or c.5254C > T (p.Q1752X), hm or c-het | 10 | SIRPT1 + SIRPT3 rs | 12–18 mths |
|
| Canada (French Canadian) | [5,38] |
several variants, c.8844delT (p.I2949FfsX2952): most common, hm or c-het | 8 or 10 | SIRPT1, 2 or 3, XPBC or DNAJ | NA |
| NA | [42] | |
c.9284dupC 9p.Ala3096Cysfs*2), hm | 10 | SIRPT3 | early child- hood |
|
| [41] | |
c.10046G > C (p.A3324P), hm | 10 | Between SIRPT3 and XPBC | 2–4 yrs |
|
| Tunisian (Tunisian) | [43] |
c.1411delT, hm | 8 | SIRPT1 | 5 yrs |
| |||
c.1155insA, hm | 8 | SIRPT1 | 1–9 yrs |
| |||
c.3662T > C (p.W1196R), hm | 10 | SIRPT1 | 10–14 yrs |
| |||
c.12846_12850delAGAG, hm | 10 | Between XPBC and DNAJ | 1–3 yrs |
|
| [44] | |
c.2439-2440delAT(V815Gfs*4), hm | 10 | SIRPT1 | 13–19 yrs |
|
| [45] |
Mutation | Exon | Domain | AOO | Clinical Symptoms | Neurological Changes | Country (Ethnicity) | Refs. |
---|---|---|---|---|---|---|---|
c.1859insC, hm | 8 | SIRPT1 | 2 yrs |
|
| Italy (Italian) | [48] |
c.4999del CAGAA5000-(p.C1679X), hm | 10 | SIRPT2 | before 10 yrs |
|
| [47] | |
c.1858C>T (p.Q620X), c.4585insA:V1528→p.fsX1540), c.het | 8 & 10, rs | SIRPT1 & SIRPT2, rs | before 2 yrs |
|
| ||
c.563G>A (p.G188E) + c.7394C>T (S2465L), c.het | 7 & 10, rs | SIRPT1 & SIRPT3, rs | 15 yrs |
|
| [49] | |
c.962G>A; p.R321Q + c.8330G>A, (R2777L), c.het | 8 & 10, rs | SIRPT1 & SIRPT3, rs | 15 mths |
|
| ||
16 novel mutations, including a large deletion, hm or c-het | 8 & 10 | SIRPT 1-2-3 or XPCB or DNAJ | 1–32 yrs |
|
| [50] | |
c.4198T>A/c.5719C>T, c.het | 10 | SIRPT2 | 15–16 yrs |
|
| [51] | |
c.13132C >T (p.R4378X), hm | 10 | DNAJ | 2 yrs |
|
| [52] | |
c.5629C>T- (p.R1877X), hm | 10 | SIRPT2 | 26 mths |
|
| [13] | |
c.600_604+1delAACAGG (p.I202fsX6), hm; 1.5 MB large deletion | 8 | SIRPT1 | 42 yrs |
|
| [53] | |
c.6680T>C (p.L2374S), hm | 10 | SIRPT2 | early childhood |
|
| [13] | |
c.10743C>T (p.Q3582X), hm | 10 | XPCPB | early childhood |
|
| [54] | |
c.11471A>G, (p.N3799D), hm | 10 | SIRPT3 | 2.5–3.5 yrs |
|
| Turkey (Turkish) | [55,56] |
c.9655_9658 delAGTT), truncation of I3199, hm | 10 | SIRPT3 | 1.5 yrs |
|
| ||
c. 2018T>C (p.C648R), hm | 8 | SIRPT1 | 2.5 yrs |
|
| ||
c. 8124delC-truncation of p.A2708, hm | 10 | SIRPT3 | 2 yrs |
|
| ||
c.1160A>G (p.F4011S), hm | 10 | between SIRPT3 & DNAJ | 1 yr |
|
| [57] | |
c. 6945A>G (p.V3369A), hm | 10 | SIRPT3 | 3–7 yrs |
|
| ||
c.12841T>A (p.K1404), c.6945A>G (p.V3369A), c.het | 10 | SIRPT2 & SIRPT3,rs | 2 yrs |
|
| ||
c.6945A>G (p.V3369A), c.12020C (p.S4007F), c.het | 10 | SIRPT3 & loop between XPCB-DNAJ | 4 yrs |
|
| ||
c.8346–8347insT (p.G2902V), hm | 10 | SIRPT2 | 2 yrs |
|
| ||
c.5677G>A (p.R3801X), hm | 10 | SIRPT3 | 3 yrs |
|
| ||
c. c.13485delC (p.K4495N), hm | 10 | DNAJ | 3 yrs |
|
| ||
p.G2772A, hm | 10 | SIRPT3 | early childhood |
|
| [58] | |
c.2182C>T (p.R728), hm | 8 | SIRPT1 | 4 yrs |
|
| [59] | |
c.12461delC (p.P4154QfsX20), hm | 10 | between XPCB & DNAJ | After 1 yr |
|
| [60] | |
Several mutations, hm or c het | 8 or 10 | SIRPT2 or 3 or between SIRPT3 & DNAJ | 1–13 yrs | patients had similar symptoms:
|
| Netherlands (Dutch, British, Turkish) | [61] |
c.3491T>A, p.M1164K, hm | 10 | SIRPT1 | 12–13 yrs |
|
| Belgium (Belgian) | [62] |
Several mutations, hm or c -het | 8 or 10, deletion of exon 3–5 | SIRPT1 or 2 or 3 or HEPN | 1–24 yrs |
|
| Belgium (Belgian, Moroccan, Serbian, Hungarian) | [63] |
c.10517T>C (p.F3506S) + chromosomal deletion, c-het | 10 | SIRPT3 | 16 yrs |
|
| [76] | |
NA | NA | NA | 1 yr |
|
| Spain (Spanish) | [77] |
c.7848C>T (p.R2556C), hm | 10 | SIRPT3 | before 1 yr |
|
| [64] | |
c.826C>T (p.R276C) + c.3904C>T (p.P1302S), c-het | 8 & 10, rs | SIRPT1+ between SIRPT3 & DNAJ, rs | early childhood |
|
| [65] | |
c.9695delC (p.T3232KfsX24),hm | 10 | SIRPT3 | 8–10 yrs |
|
| Greece (Greek) | [66] |
c.9804_9805insC, (p.S3268 _Ifs), hm | 10 | SIRPT3 | 1.5–5 yrs |
|
| Poland (Polish) | [67] |
c.72276C>T (p.R2426X) | 10 | SIRPT3 | 32 yrs |
|
| Russia (Russian) | [68] |
c.13352T>C (p.L4451P) + c.6890T>G (p.L2297W), c.het | 10 | HEPN+ SIRPT2, rs | before 10 yrs |
|
| Norway (Norwegian) | [69] |
17 novel SACS mutations, hm or c-het | 8 + 9 + 10 | SIRT1 or 2 or 3 or DNAJ or HEPN | 1–30 yrs |
|
| Germany (German, Turkish, Greek, Macedonian) | [4] |
9 different mutations in 6 families, hm or c-het | 8 or 10 | SIRT1 or 2 or 3 or DNAJ or HEPN | 2–15 yrs |
|
| Germany (German, Italian, Romanian, Turkish, Arabic) | [70] |
c.2076delG (p.T692) + c.3965_3966del (p.G1322Vfs*1343), c-het | 8 & 10 | SIRT1+ SIRPT2, rs | 19–26 yrs |
|
| UK (British) | [71] |
20 mutations, 11 novel mutations, hm or c-het | 10 | SIRT1 or 2 or 3 or DNAJ or HEPN | 1–46 yrs |
|
| [72] | |
c.5744_5745delAT (p.H1915Rfs*19),hm | 10 | SIRPT2 | 9–19 yrs |
|
| France (French) | [73] |
p.E1100K + p.N1489S + p.M1359T, c-het | 10 | SIRT1+ SIRPT2, rs | 6–15 yrs |
|
| Finland (Finnish) | [74] |
c.13721T/G (p.F4574C), hm | 10 | HEPN | 37 yrs |
|
| Macedonia (Macedonian) | [75] |
Mutation | Exon | Domain | AOO | Clinical Symptoms | Neurological Changes | Country (Ethnicity) | References |
---|---|---|---|---|---|---|---|
p.3774C>T, p.Q1198X, c.het | 10 | XPCB & SIRPT1, rs | 9 yrs |
|
| Japan (Japanese) | [78] |
c.2951_2952delAG(p.Q984GfsX986)+3922delT(p.1308LfsX1326), c. het | 10 | SIRPT1 + between SIRPT3 & XPBC, rs | 15–20 yrs |
|
| [81] | |
c.32627-32636delACACTGTTAC(p.W395-fsX407), c.31760delT (p.V687-fsX713), c.het | 8 | SIRPT1 | under 10 yrs |
|
| [79] | |
c.6543delA, (p.R2002X), hm | 10 | SIRPT2 | early childhood |
|
| [80] | |
c.5988-9del CT, hm | 10 | SIRPT2 | early childhood |
|
| [81] | |
c. 987C>T (p.F304S), hm | 8 | SIRPT1 | before 10 yrs |
|
| [82] | |
c. 6355C>T (p.R2119X), hm | 10 | SIRPT2 | 20s |
|
| [83] | |
c.482delA (p.L802P), c.2405T>C (p.N161fsX175), c-het | 10 & 7 rs | SIRPT1 | late 10s- early 20s |
|
| [85] | |
c.12976A/G (p.K4326Q), c.4233-4236 delACTT (p.L1412Kfs*16), c-het | 10 | DNAJ + SIRPT2, rs | ~22 yrs |
|
| [85] | |
c.3769 G>T (p.G1257X)+11361–2insT(p.R3788SfsX3820), c-het | 10 | SIRPT2 & SIRPT3, rs | 12 yrs |
|
| [86] | |
c.414 C>G (p.Y138X) +5263–4delAA (p.K1755VfsX1775), c-het | 7 & 10, rs | SIRPT1 & SIRPT2, rs | 12–19 yrs |
|
| [87,88] | |
c.4756_4760del (p.N1586Yfs*3)+ putative noncoding mutation, c-het | 10 | SIRPT2 | early childhood |
|
| Korea (Korean) | [89] |
c.8844delT (p.I2949Ffs*4) + c.11781_11782dupGC (p.P3928Rfs*17), c-het | 10 | SIRPT3 +between XPCB & DNAJ, rs | ~20 yrs |
|
| [90] | |
c.7272C>A (p.C2424X), c.11319_11321del (p.R3774del), c-het | 10 | SIRPT3 +XPCB, rs | ~10 yrs |
|
| [91] | |
c.11803C>T (p.Q3935X)+ 1.33Mb deletion, c-het | 10 | between SIRPT3 & XPCB | 6 yrs |
|
| China (Chinese) | [92] |
c.12637 _12638delGA (p.Q4213Rfs*3)+ c.11274_11276delAAC (p.I3758_ TdelinsM), c-het | 10 | between XPCB & DNAJ + XPCB, rs | 10’s |
|
| [93] | |
c. 8000T>C (p.F2667S), c. 10685_10689del (p.F3562X), c-het | 10 | SIRPT3 + between XPCB & DNAJ + XPCB, rs | early childhood |
|
| [94] | |
c.5236dupA (p.T1746fs)+ c.13085T/G (p.I4362R), c-het | 10 | SIRPT2 +DNAJ, rs | NA |
|
| [96] | |
c.9019C>T, p.P3007S and c.10174_10183del, p.H3392fs | 10 | SIRPT2 + between XPCB & DNAJ | early childhood |
|
| [95] | |
c.1773C>A (p.S578X) + c.8088_8089 insCA (p.M2697Q fs*43), c-het | 8 & 10, rs | SIRPT1 + SIRPT3, rs | 6 yrs |
|
| ||
c.5692 G>T, p.E1898X; c.12673-12677 del TATCA, p.Y4225D fs*6-c-het | 10 | SIRPT1 +DNAJ, rs | Early childhood |
|
| [97] | |
c.1773C>A, p.S578X; c.8088-8089 in. CA, p.M2697Q fs*4 | 10 | SIRPT1 + SIRPT3, rs | 6 yrs |
|
| ||
c.382_383del (p.Q128Sfs*2), hm | 7 | SIRPT1 | 2 yrs |
|
| Thailand (Thai) | [98] |
c.5824_5827delTACT (p.Y1942Mfs*9), hm | 10 | SIRPT2 | early teens |
|
| Kuwait (Kuwait) | [99] |
c.429_430delTT (p.W144VfsX39), hm | 7 | SIRPT1 | 3 yrs |
|
| Iran (Iranian) | [100] |
c.4117_4118delGCinsAG (p.A1373R), hm | 10 | SIRPT2 | early childhood |
|
| [101] | |
c.14329fs*2725 (p.R707Kfs*6), hm | 10 | SIRPT2SIRPT1 | 9–15 yrs |
|
| India (Indian) | [102] |
c.11690_11693dupGTGA (p.N3898QfsX2),hm | 10 | XPCB | 4 yrs |
|
| [103] | |
c.8605delT (p.C2869VfsX15), hm | 10 | SIRPT3 | 14 mths |
|
| [104] | |
c.8793 delA, hm | 10 | SIRPT1 | early childhood |
|
| [105] | |
c. 4232T>G + c.8132C>T, c-het | 10 | SIRPT2 + SIRPT3, rs | 3 yrs |
|
| [106] | |
c.2656C>T (p.Q886*), hm | 10 | SIRPT1 | 11–12 yrs |
|
| Pakistan (Pakistani) | [107] |
c.4756_4760delAATCA (p.N1586Yfs*3), hm | 10 | SIRPT2 | 9–10 yrs |
|
| ||
c.9119dupA (p.N3040Kfs*4), hm | 10 | SIRPT3 | 1.5 yrs |
|
| [108] | |
p.N2380K & p.D3269N, c-het | 10 | SIRPT2 + SIRPT3, rs | 16 mths |
|
| Israel (Ashkenazi Jews) | [109] |
Mutation | Exon | Domain | AOO | Clinical Symptoms | Neurological Changes | Country (Ethnicity) | Refs |
---|---|---|---|---|---|---|---|
c.3484G>T (p.E1162X), & c. 11707C>T (p.R3903X), c-het | 10 | SIRPT1+ between SIRPT3 & XPBC, rs | 2.5–3.5 yrs |
|
| USA (American) | [110] |
c.11637_11638delAG (p.R3879fs), hm | 10 | SIRPT3 & XPBC, rs | 4 yrs |
|
| [111] | |
Chr13 duplication | NA | NA | 13 yrs |
|
| [112] | |
c.4744G>A (p.D1582N) + c.7205_7206delTT (p.L2402Rfs*6), c-het | 10 | SIRPT2 + SIRPT3, rs | 2 yrs |
|
| USA (American or mixed European) | [113] |
c.11824dup (p.M3942Nfs*4), hm | 10 | XPCB | 11 yrs |
|
| USA (African American) | [114] |
11 SACS variants in 39 patients, hm or c-het | 8 or 10 | SIRPT 1-3, XPBC or HEPN | NA |
|
| USA (NA) | [115] |
NA | NA | NA | early childhood |
|
| Brazil (Brazilian) | [116] |
c.5150_5151insA | 10 | SIRPT2 | early childhood |
|
| Brazil (German) | [117] |
Several variants, including p.L393Cfs*17 & p.N2760Mfs*6 | 8 or 10, rs | SIRPT 1-3 or XPBC | 1–44 yrs |
|
| Brazil (Brazilian) | [118] |
c.8107C>T (p.R2703C) +c.922C>T-(p.L308F), hm | 10 + 8, rs | SIRPT3 + SIRPT1, rs | 8–9 yrs |
|
| [119] | |
c.7962T>G (p.Y2654X), hm | 10 | SIRPT3 | 20’s |
|
| New Zealand (Maori & English) | [120] |
5. Potential Involvement of SACS in Other Neurodegenerative Diseases
6. ARSACS Diagnosis and Potential Therapeutics
7. Discussion and Future Insights
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Bagaria, J.; Bagyinszky, E.; An, S.S.A. Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration. Int. J. Mol. Sci. 2022, 23, 552. https://doi.org/10.3390/ijms23010552
Bagaria J, Bagyinszky E, An SSA. Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration. International Journal of Molecular Sciences. 2022; 23(1):552. https://doi.org/10.3390/ijms23010552
Chicago/Turabian StyleBagaria, Jaya, Eva Bagyinszky, and Seong Soo A. An. 2022. "Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration" International Journal of Molecular Sciences 23, no. 1: 552. https://doi.org/10.3390/ijms23010552
APA StyleBagaria, J., Bagyinszky, E., & An, S. S. A. (2022). Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration. International Journal of Molecular Sciences, 23(1), 552. https://doi.org/10.3390/ijms23010552