1n2k

Structural highlights

Disease

[ARSA_HUMAN] Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) [MIM:250100]. MLD is a disease due to a lysosomal storage defect. It is characterized by intralysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues, with a diffuse loss of myelin in the central nervous system. Progressive demyelination causes a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Three forms of the disease can be distinguished according to the age at onset: late-infantile, juvenile and adult.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41]} Arylsulfatase A activity is defective in multiple sulfatase deficiency (MSD) [MIM:272200]. A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. Note=Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1. SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine.^{[42] [43]}

Function

[ARSA_HUMAN] Hydrolyzes cerebroside sulfate.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Kondo R, Wakamatsu N, Yoshino H, Fukuhara N, Miyatake T, Tsuji S. Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy. Am J Hum Genet. 1991 May;48(5):971-8. PMID:1673291
2. ↑ Gieselmann V, Fluharty AL, Tonnesen T, Von Figura K. Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. Am J Hum Genet. 1991 Aug;49(2):407-13. PMID:1678251
3. ↑ Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 1991 Jan 3;324(1):18-22. PMID:1670590
4. ↑ Kappler J, von Figura K, Gieselmann V. Late-onset metachromatic leukodystrophy: molecular pathology in two siblings. Ann Neurol. 1992 Mar;31(3):256-61. PMID:1353340 doi:http://dx.doi.org/10.1002/ana.410310305
5. ↑ Kreysing J, Bohne W, Bosenberg C, Marchesini S, Turpin JC, Baumann N, von Figura K, Gieselmann V. High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy. Am J Hum Genet. 1993 Aug;53(2):339-46. PMID:8101038
6. ↑ Hasegawa Y, Kawame H, Eto Y. Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy. DNA Cell Biol. 1993 Jul-Aug;12(6):493-8. PMID:8101083
7. ↑ Barth ML, Fensom A, Harris A. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum Genet. 1993 Mar;91(1):73-7. PMID:8095918
8. ↑ Honke K, Kobayashi T, Fujii T, Gasa S, Xu M, Takamaru Y, Kondo R, Tsuji S, Makita A. An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A. Hum Genet. 1993 Nov;92(5):451-6. PMID:7902317
9. ↑ Barth ML, Fensom A, Harris A. Missense mutations in the arylsulphatase A genes of metachromatic leukodystrophy patients. Hum Mol Genet. 1993 Dec;2(12):2117-21. PMID:7906588
10. ↑ Harvey JS, Nelson PV, Carey WF, Robertson EF, Morris CP. An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy. Hum Mutat. 1993;2(4):261-7. PMID:8104633 doi:http://dx.doi.org/10.1002/humu.1380020405
11. ↑ Hasegawa Y, Kawame H, Ida H, Ohashi T, Eto Y. Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing. Hum Genet. 1994 Apr;93(4):415-20. PMID:7909527
12. ↑ Heinisch U, Zlotogora J, Kafert S, Gieselmann V. Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet. 1995 Jan;56(1):51-7. PMID:7825603
13. ↑ Kafert S, Heinisch U, Zlotogora J, Gieselmann V. A missense mutation P136L in the arylsulfatase A gene causes instability and loss of activity of the mutant enzyme. Hum Genet. 1995 Feb;95(2):201-4. PMID:7860068
14. ↑ Barth ML, Fensom A, Harris A. Identification of seven novel mutations associated with metachromatic leukodystrophy. Hum Mutat. 1995;6(2):170-6. PMID:7581401 doi:http://dx.doi.org/10.1002/humu.1380060210
15. ↑ Tsuda T, Hasegawa Y, Eto Y. Two novel mutations in a Japanese patient with the late-infantile form of metachromatic leukodystrophy. Brain Dev. 1996 Sep-Oct;18(5):400-3. PMID:8891236
16. ↑ Regis S, Filocamo M, Stroppiano M, Corsolini F, Gatti R. A T > C transition causing a Leu > Pro substitution in a conserved region of the arylsulfatase A gene in a late infantile metachromatic leukodystrophy patient. Clin Genet. 1997 Jul;52(1):65-7. PMID:9272717
17. ↑ Draghia R, Letourneur F, Drugan C, Manicom J, Blanchot C, Kahn A, Poenaru L, Caillaud C. Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene. Hum Mutat. 1997;9(3):234-42. PMID:9090526 doi:<234::AID-HUMU4>3.0.CO;2-7 10.1002/(SICI)1098-1004(1997)9:3<234::AID-HUMU4>3.0.CO;2-7
18. ↑ Regis S, Filocamo M, Stroppiano M, Corsolini F, Caroli F, Gatti R. A 9-bp deletion (2320del9) on the background of the arylsulfatase A pseudodeficiency allele in a metachromatic leukodystrophy patient and in a patient with nonprogressive neurological symptoms. Hum Genet. 1998 Jan;102(1):50-3. PMID:9490297
19. ↑ Gomez-Lira M, Perusi C, Mottes M, Pignatti PF, Manfredi M, Rizzuto N, Salviati A. Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation. Hum Genet. 1998 Apr;102(4):459-63. PMID:9600244
20. ↑ Coulter-Mackie MB, Gagnier L. Two novel mutations in the arylsulfatase A gene associated with juvenile (R390Q) and adult onset (H397Y) metachromatic leukodystrophy. Hum Mutat. 1998;Suppl 1:S254-6. PMID:9452102
21. ↑ Kurosawa K, Ida H, Eto Y. Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy: identification of two novel mutations. J Inherit Metab Dis. 1998 Oct;21(7):781-2. PMID:9819708
22. ↑ Marcao A, Amaral O, Pinto E, Pinto R, Sa Miranda MC. Metachromatic leucodystrophy in Portugal-finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC. Mutations in brief no. 232. Online. Hum Mutat. 1999;13(4):337-8. PMID:10220151 doi:<337::AID-HUMU12>3.0.CO;2-F 10.1002/(SICI)1098-1004(1999)13:4<337::AID-HUMU12>3.0.CO;2-F
23. ↑ Gort L, Coll MJ, Chabas A. Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. Hum Mutat. 1999;14(3):240-8. PMID:10477432 doi:<240::AID-HUMU7>3.0.CO;2-L 10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L
24. ↑ Halsall DJ, Halligan EP, Elsey TS, Cox TM. Metachromatic leucodystrophy: a newly identified mutation in arylsulphatase A, D281Y, found as a compound heterozygote with I179L in an adult onset case. Hum Mutat. 1999 Nov;14(5):447. PMID:10533072 doi:<447::AID-HUMU12>3.0.CO;2-1 10.1002/(SICI)1098-1004(199911)14:5<447::AID-HUMU12>3.0.CO;2-1
25. ↑ Qu Y, Shapira E, Desnick RJ. Metachromatic leukodystrophy: subtype genotype/phenotype correlations and identification of novel missense mutations (P148L and P191T) causing the juvenile-onset disease. Mol Genet Metab. 1999 Jul;67(3):206-12. PMID:10381328 doi:10.1006/mgme.1999.2865
26. ↑ Hermann S, Schestag F, Polten A, Kafert S, Penzien J, Zlotogora J, Baumann N, Gieselmann V. Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy. Am J Med Genet. 2000 Mar 6;91(1):68-73. PMID:10751093
27. ↑ Felice KJ, Gomez Lira M, Natowicz M, Grunnet ML, Tsongalis GJ, Sima AA, Kaplan RF. Adult-onset MLD: a gene mutation with isolated polyneuropathy. Neurology. 2000 Oct 10;55(7):1036-9. PMID:11061266
28. ↑ Arbour LT, Silver K, Hechtman P, Treacy EP, Coulter-Mackie MB. Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol. 2000 Aug;23(2):173-6. PMID:11020646
29. ↑ Comabella M, Waye JS, Raguer N, Eng B, Dominguez C, Navarro C, Borras C, Krivit W, Montalban X. Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family. Ann Neurol. 2001 Jul;50(1):108-12. PMID:11456299
30. ↑ Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M. Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. Hum Genet. 2002 Apr;110(4):351-5. Epub 2002 Mar 8. PMID:11941485 doi:10.1007/s00439-002-0701-y
31. ↑ Marcao A, Simonis H, Schestag F, Sa Miranda MC, Gieselmann V. Biochemical characterization of two (C300F, P425T) arylsulfatase a missense mutations. Am J Med Genet A. 2003 Jan 30;116A(3):238-42. PMID:12503099 doi:10.1002/ajmg.a.10822
32. ↑ Marcao A, Azevedo JE, Gieselmann V, Sa Miranda MC. Oligomerization capacity of two arylsulfatase A mutants: C300F and P425T. Biochem Biophys Res Commun. 2003 Jun 20;306(1):293-7. PMID:12788103
33. ↑ Eng B, Nakamura LN, O'Reilly N, Schokman N, Nowaczyk MM, Krivit W, Waye JS. Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD). Hum Mutat. 2003 Nov;22(5):418-9. PMID:14517960 doi:10.1002/humu.9190
34. ↑ Olkhovich NV, Takamura N, Pichkur NA, Gorovenko NG, Aoyagi K, Yamashita S. Novel mutations in arylsulfatase A gene in three Ukrainian families with metachromatic leukodystrophy. Mol Genet Metab. 2003 Nov;80(3):360-3. PMID:14680985 doi:10.1016/j.ymgme.2003.08.004
35. ↑ Berna L, Gieselmann V, Poupetova H, Hrebicek M, Elleder M, Ledvinova J. Novel mutations associated with metachromatic leukodystrophy: phenotype and expression studies in nine Czech and Slovak patients. Am J Med Genet A. 2004 Sep 1;129A(3):277-81. PMID:15326627 doi:10.1002/ajmg.a.30118
36. ↑ Gallo S, Randi D, Bertelli M, Salviati A, Pandolfo M. Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene. J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):655-7. PMID:15026521
37. ↑ Marcao AM, Wiest R, Schindler K, Wiesmann U, Weis J, Schroth G, Miranda MC, Sturzenegger M, Gieselmann V. Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene. Arch Neurol. 2005 Feb;62(2):309-13. PMID:15710861 doi:10.1001/archneur.62.2.309
38. ↑ Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, Di Rocco M, Parenti G, Deodato F, Leuzzi V, Biancheri R, Filocamo M. Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. Hum Mutat. 2008 Nov;29(11):E220-30. doi: 10.1002/humu.20851. PMID:18693274 doi:10.1002/humu.20851
39. ↑ Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A. Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. Hum Mutat. 2009 Oct;30(10):E936-45. doi: 10.1002/humu.21093. PMID:19606494 doi:10.1002/humu.21093
40. ↑ Lugowska A, Ploski R, Wlodarski P, Tylki-Szymanska A. Molecular bases of metachromatic leukodystrophy in Polish patients. J Hum Genet. 2010 Jun;55(6):394-6. doi: 10.1038/jhg.2010.25. Epub 2010 Mar 26. PMID:20339381 doi:10.1038/jhg.2010.25
41. ↑ Hayashi T, Nakamura M, Ichiba M, Matsuda M, Kato M, Shiokawa N, Shimo H, Tomiyasu A, Mori S, Tomiyasu Y, Ishizuka T, Inamori Y, Okamoto Y, Umehara F, Arimura K, Nakabeppu Y, Sano A. Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case. Psychiatry Clin Neurosci. 2011 Feb;65(1):105-8. doi:, 10.1111/j.1440-1819.2010.02169.x. PMID:21265945 doi:10.1111/j.1440-1819.2010.02169.x
42. ↑ Schmidt B, Selmer T, Ingendoh A, von Figura K. A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell. 1995 Jul 28;82(2):271-8. PMID:7628016
43. ↑ Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R, Di Domenico C, Di Natale P, Mankad A, Cox B, Uziel G, Mancini GM, Zammarchi E, Donati MA, Kleijer WJ, Filocamo M, Carrozzo R, Carella M, Ballabio A. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004 Jun;23(6):576-81. PMID:15146462 doi:10.1002/humu.20040
44. ↑ Chruszcz M, Laidler P, Monkiewicz M, Ortlund E, Lebioda L, Lewinski K. Crystal structure of a covalent intermediate of endogenous human arylsulfatase A. J Inorg Biochem. 2003 Aug 1;96(2-3):386-92. PMID:12888274