Spinal muscular atrophy: State-of-the-art and therapeutic perspectives

Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders

Volumn 3, Issue 2, 2002, Pages 87-95

  Wirth, Brunhilde ^a  

^a UNIVERSITY OF BONN   (Germany)

Author keywords

Exonic splicing enhancer (ESE); Molecular basis; Somatic gene therapy; Spinal muscular atrophy (SMA); Survival motor neuron gene (SMN)

Indexed keywords

ACLARUBICIN; ANTISENSE OLIGONUCLEOTIDE; BUTYRIC ACID; COMPLEMENTARY RNA; MESSENGER RNA; TRANSACTIVATOR PROTEIN;

ALPHA NERVE FIBER; ALTERNATIVE RNA SPLICING; ANIMAL EXPERIMENT; ANIMAL MODEL; AUTOSOMAL RECESSIVE DISORDER; CELL DEGENERATION; DISEASE SEVERITY; DRUG HALF LIFE; DRUG MECHANISM; EXON; GENE DELETION; GENE MUTATION; GENE THERAPY; HOMOZYGOSITY; HUMAN; MOUSE; MUSCLE ATROPHY; MUSCLE WEAKNESS; NONHUMAN; NUCLEIC ACID BASE SUBSTITUTION; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SPINAL CORD MOTONEURON; SPINAL CORD VENTRAL HORN; SPINAL MUSCULAR ATROPHY; VOLUNTARY MOVEMENT;

ANIMALS; CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN; DISEASE MODELS, ANIMAL; GENE THERAPY; GENOTYPE; HUMANS; MUSCULAR ATROPHY, SPINAL; MUTATION; NERVE TISSUE PROTEINS; PHENOTYPE; RNA-BINDING PROTEINS;

EID: 0036393291     PISSN: 14660822     EISSN: None     Source Type: Journal    
DOI: 10.1080/146608202760196057     Document Type: Review

References (103)

1. Munsat TL, Davies KE. International SMA consortium meeting (26-28 June 1992, Bonn, Germany). Neuromuscul Disord 1992; 2: 423-428.
2. Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995; 52: 518-523.
3. Engel M. Selective and non-selective susceptibility to muscle fibre types. Arch Neurol 1970; 22: 761-763.
4. Gilliam TC, Brzustowicz LM, Castilla LH et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990; 345: 823-825.
5. Melki J, Sheth P, Abdelhak S et al. Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators. Lancet 1990; 336: 271-273.
6. Melki J, Abdelhak S, Sheth P et al. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature 1990; 344: 767-768.
7. Brzustowicz LM, Lehner T, Castilla LH et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 1990; 344: 540-541.
8. Lefebvre S, Burglen L, Reboullet S et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80: 155-165.
9. Burglen L, Lefebvre S, Clermont O et al. Structure and organization of the human survival motor neurone (SMN) gene. Genomics 1996; 32: 479-482.
10. Chen Q, Baird SD, Mahadevan M et al. Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN and NAIP. Genomics 1998; 48: 121-127.
11. Monani UR, Lorson CL, Parsons DW et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8: 1177-1183.
12. Scheffer H, Cobben JM, Matthijs G, Wirth B. Best practice guidelines for molecular analysis in spinal muscular atrophy. Eur J Hum Genet 2001; 9: 484-491.
13. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15: 228-237.
14. Brahe C, Servidei S, Zappata S, Ricci E, Tonali P, Neri G. Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 1995; 346: 741-742.
15. Zerres K, Rudnik-Schoneborn S, Forkert R, Wirth B. Genetic basis of adult-onset spinal muscular atrophy. Lancet 1995; 346: 1162.
16. Wirth B, Herz M, Wetter A et al. Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am J Hum Genet 1999; 64: 1340-1356.
17. McAndrew PE, Parsons DW, Simard LR et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet 1997; 60: 1411-1422.
18. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002; 70: 358-368.
19. Veldink JH, van den Berg LH, Cobben JM et al. Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS. Neurology 2001; 56: 749-752.
20. Wirth B, Tessarolo D, Hahnen E et al. Different entities of proximal spinal muscular atrophy within one family. Hum Genet 1997; 100: 676-680.
21. Burghes AH. When is a deletion not a deletion? When it is converted. Am J Hum Genet 1997; 61: 9-15.
22. Wirth B, Schmidt T, Hahnen E et al. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling. Am J Hum Genet 1997; 61: 1102-1111.
23. Wirth B, Hahnen E, Morgan K, et al. Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs. Hum Mol Genet 1995; 4: 1273-1284.
24. Hahnen E, Schonling J, Rudnik-Schoneborn S, Zerres K, Wirth B. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am J Hum Genet 1996; 59: 1057-1065.
25. Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet 1997; 61: 40-50.
26. Kelter AR, Herchenbach J, Wirth B. The transcription factor-like nuclear regulator (TFNR) contains a novel 55-amino-acid motif repeated nine times and maps closely to SMN1. Genomics 2000; 70: 315-326.
27. Schrank B, Gotz R, Gunnersen JM et al. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 1997; 94: 9920-9925.
28. Hahnen E, Forkert R, Marke C et al. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum Mol Genet 1995; 4: 1927-1933.
29. Cobben JM, van der Steege G, Grootscholten P, de Visser M, Scheffer H, Buys CH. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. Am J Hum Genet 1995; 57: 805-808.
30. Wang CH, Xu J, Carter TA et al. Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy. Hum Mol Genet 1996; 5: 359-365.
31. Mailman MD, Heinz JW, Papp AC et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 2002; 4: 20-26.
32. van der Steege G, Grootscholten PM, van der Vlies P et al. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 1995; 345: 985-986.
33. Wirth B, Rudnik-Schoneborn S, Hahnen E, Rohrig D, Zerres K. Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases. Prenat Diagn 1995; 15: 407-417.
34. Milunsky JM, Cheney SM. Prenatal diagnosis of spinal muscular atrophy by direct molecular analysis: efficacy and potential pitfalls. Genet Test 1999; 3: 255-258.
35. Fallon L, Harton GL, Sisson ME et al. Preimplantation genetic diagnosis for spinal muscular atrophy type I. Neurology 1999; 53: 1087-1090.
36. Dreesen JC, Bras M, de Die-Smulders C et al. Preimplantation genetic diagnosis of spinal muscular atrophy. Mol Hum Reprod 1998; 4: 881-885.
37. Daniels G, Pettigrew R, Thornhill A et al. Six unaffected livebirths following preimplantation diagnosis for spinal muscular atrophy. Mol Hum Reprod 2001; 7: 995-1000.
38. Scheffer H, Cobben JM, Mensink RG, Stulp RP, van der Steege G, Buys CH. SMA carrier testing - validation of hemizygous SMN exon 7 deletion test for the identification of proximal spinal muscular atrophy carriers and patients with a single allele deletion. Eur J Hum Genet 2000; 8: 79-86.
39. Burglen L, Amiel J, Viollet L et al. Survival motor neuron gene-deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association. J Clin Invest 1996; 98: 1130-1132.
40. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999; 96: 6307-6311.
41. Lorson CL, Androphy EJ. An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 2000; 9: 259-265.
42. Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet 2002; 30: 377-384.
43. Hofmann Y, Lorson CL, Stamm S, Androphy EJ, Wirth B. Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc Natl Acad Sci USA 2000; 97: 9618-9623.
44. Young PJ, DiDonato CJ, Hu D, Kothary R, Androphy EJ, Lorson CL. SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2beta1. Hum Mol Genet 2002; 11: 577-587.
45. Hofmann Y, Wirth B. Identification of hnRNP-G as a novel trans-factor that promotes inclusion of the alternatively spliced exon 7 of SMN2 by direct interaction with Htra2-β1. Hum Mol Genet 2002 (submitted).
46. Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci USA 2001; 98: 9808-9813.
47. Andreassi C, Jarecki J, Zhou J et al. Aclarubicin treatment restores SMN levels to cells derived from type 1 spinal muscular atrophy patients. Hum Mol Genet 2001; 10: 2841-2849.
48. Zhang ML, Lorson CL, Androphy EJ, Zhou J. An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA. Gene Ther 2001; 8: 1532-1538.
49. Lefebvre S, Burlet P, Liu Q et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997; 16: 265-269.
50. Coovert DD, Le TT, McAndrew PE et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997; 6: 1205-1214.
51. Lorson CL, Strasswimmer J, Yao JM et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet 1998; 19: 63-66.
52. Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. Embo J 1996; 15: 3555-3565.
53. Carvalho T, Almeida F, Calapez A, Lafarga M, Berciano MT, Carmo-Fonseca M. The spinal muscular atrophy disease gene product, SMN: A link between snRNP biogenesis and the Cajal (coiled) body. J Cell Biol 1999; 147: 715-728.
54. Liu Q, Fischer U, Wang F, Dreyfuss G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 1997; 90: 1013-1021.
55. Fischer U, Liu Q, Dreyfuss G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 1997; 90: 1023-1029.
56. Charroux B, Pellizzoni L, Perkinson RA, Shevchenko A, Mann M, Dreyfuss G. Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems. J Cell Biol 1999; 147: 1181-1194.
57. Campbell L, Hunter KM, Mohaghegh P, Tinsley JM, Brasch MA, Davies KE. Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation? Hum Mol Genet 2000; 9: 1093-1100.
58. Charroux B, Pellizzoni L, Perkinson RA et al. Gemin4. A novel component of the SMN complex that is found in both gems and nucleoli. J Cell Biol 2000; 148: 1177-1186.
59. Gubitz AK, Mourelatos Z, Abel L, Rappsilber J, Mann M, Dreyfuss G. Gemin5: A novel WD repeat protein component of the SMN complex that binds Sm proteins. J Biol Chem 2002; 277: 5631-5636.
60. Pellizzoni L, Baccon J, Rappsilber J, Mann M, Dreyfuss G. Purification of native SMN complexes and identification of Gemin6 as a novel component. J Biol Chem 2002; 277: 7540-7545.
61. Selenko P, Sprangers R, Stier G, Buhler D, Fischer U, Sattler M. SMN tudor domain structure and its interaction with the Sm proteins. Nat Struct Biol 2001; 8: 27-31.
62. Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 1998; 95: 615-624.
63. Friesen WJ, Dreyfuss G. Specific sequences of the Sm and Sm-like (Lsm) proteins mediate their interaction with the spinal muscular atrophy disease gene product (SMN). J Biol Chem 2000; 275: 26370-26375.
64. Mourelatos Z, Abel L, Yong J, Kataoka N, Dreyfuss G. SMN interacts with a novel family of hnRNP and spliceosomal proteins. Embo J 2001; 20: 5443-5452.
65. Rossoll W, Kroning AK, Ohndorf UM, Steegborn C, Jablonka S, Sendtner M. Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum Mol Genet 2002; 11: 93-105.
66. Gangwani L, Mikrut M, Theroux S, Sharma M, Davis RJ. Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein. Nat Cell Biol 2001; 3: 376-383.
67. Pellizzoni L, Baccon J, Charroux B, Dreyfuss G. The survival of motor neurons (SMN) protein interacts with the snoRNP proteins fibrillarin and GAR1. Curr Biol 2001; 11: 1079-1088.
68. Jones KW, Gorzynski K, Hales CM et al. Direct interaction of the spinal muscular atrophy disease protein SMN with the small nucleolar RNA-associated protein fibrillarin. J Biol Chem 2001; 276: 38645-38651.
69. Pellizzoni L, Charroux B, Rappsilber J, Mann M, Dreyfuss G. A functional interaction between the survival motor neuron complex and RNA polymerase II. J Cell Biol 2001; 152: 75-85.
70. Strasswimmer J, Lorson CL, Breiding DE et al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum Mol Genet 1999; 8: 1219-1226.
71. Young PJ, Le TT, thi Man N, Burghes AH, Morris GE. The relationship between SMN, the spinal muscular atrophy protein, and nuclear coiled bodies in differentiated tissues and cultured cells. Exp Cell Res 2000; 256: 365-374.
72. Young PJ, Le TT, Dunckley M, Nguyen TM, Burghes AH, Morris GE. Nuclear gems and Cajal (coiled) bodies in fetal tissues: nucleolar distribution of the spinal muscular atrophy protein, SMN. Exp Cell Res 2001; 265: 252-261.
73. Tucker KE, Berciano MT, Jacobs EY et al. Residual Cajal bodies in coilin knockout mice fail to recruit Sm snRNPs and SMN, the spinal muscular atrophy gene product. J Cell Biol 2001; 154: 293-307.
74. Hebert MD, Szymczyk PW, Shpargel KB, Matera AG. Coilin forms the bridge between Cajal bodies and SMN, the spinal muscular atrophy protein. Genes Dev 2001; 15: 2720-2729.
75. Frugier T, Tiziano FD, Cifuentes-Diaz C et al. Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy. Hum Mol Genet 2000; 9: 849-858.
76. Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y. Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy. Nature 1997; 390: 413-417.
77. Sato K, Eguchi Y, Kodama TS, Tsujimoto Y. Regions essential for the interaction between Bcl-2 and SMN, the spinal muscular atrophy disease gene product. Cell Death Differ 2000; 7: 374-383.
78. Young PJ, Day PM, Zhou J, Androphy EJ, Morris GE, Lorson CL. A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem 2002; 277: 2852-2859.
79. Coovert DD, Le TT, Morris GE et al. Does the survival motor neuron protein (SMN) interact with Bcl-2? J Med Genet 2000; 37: 536-539.
80. Kurihara N, Menaa C, Maeda H, Haile DJ, Reddy SV. Osteoclast-stimulating factor interacts with the spinal muscular atrophy gene product to stimulate osteoclast formation. J Biol Chem 2001; 276: 41035-41039.
81. Giesemann T, Rathke-Hartlieb S, Rothkegel M et al. A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems. J Biol Chem 1999; 274: 37908-37914.
82. Williams BY, Hamilton SL, Sarkar HK. The survival motor neuron protein interacts with the transactivator FUSE binding protein from human fetal brain. FEBS Lett 2000; 470: 207-210.
83. Pellizzoni L, Charroux B, Dreyfuss G. SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins. Proc Natl Acad Sci USA 1999; 96: 11167-11172.
84. Buhler D, Raker V, Luhrmann R, Fischer U. Essential role for the tudor domain of SMN in spliceosomal U snRNP assembly: implications for spinal muscular atrophy. Hum Mol Genet 1999; 8: 2351-2357.
85. Friesen WJ, Massenet S, Paushkin S, Wyce A, Dreyfuss G. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol Cell 2001; 7: 1111-1117.
86. Brahms H, Meheus L, de Brabandere V, Fischer U, Luhrmann R. Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein. Rna 2001; 7: 1531-1542.
87. Jablonka S, Bandilla M, Wiese S et al. Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. Hum Mol Genet 2001; 10: 497-505.
88. Jablonka S, Schrank B, Kralewski M, Rossoll W, Sendtner M. Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum Mol Genet 2000; 9: 341-346.
89. Monani UR, Sendtner M, Coovert DD et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 2000; 9: 333-339.
90. Hsieh-Li HM, Chang JG, Jong YJ et al. A mouse model for spinal muscular atrophy. Nat Genet 2000; 24: 66-70.
91. Cifuentes-Diaz C, Frugier T, Tiziano FD et al. Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J Cell Biol 2001; 152: 1107-1114.
92. Rudnik-Schoneborn S, Lutzenrath S, Borkowska J, Karwanska A, Hausmanowa-Petrusewicz I, Zerres K. Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I-III from the point of view of progression and severity. Eur Neurol 1998; 39: 154-162.
93. Kruh J. Effects of sodium butyrate, a new pharmacological agent, on cells in culture. Mol Cell Biochem 1982; 42: 65-82.
94. Lim SR, Hertel KJ. Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J Biol Chem 2001; 276: 45476-45483.
95. Baron-Delage S, Abadie A, Echaniz-Laguna A, Melki J, Beretta L. Interferons and IRF-1 induce expression of the survival motor neuron (SMN) genes. Mol Med 2000; 6: 957-968.
96. Rodrigues NR, Owen N, Talbot K Ignatius J, Dubowitz V, Davies KE. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum Mol Genet 1995; 4: 631-634.
97. Bussaglia E, Clermont O, Tizzano E et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat Genet 1995; 11: 335-337.
98. van der Steege G, Grootscholten PM, Cobben JM et al. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am J Hum Genet 1996; 59: 834-838.
99. Carter TA, Bonnemann CG, Wang CH et al. A multicopy transcription-repair gene, BTF2p44, maps to the SMA region and demonstrates SMA associated deletions. Hum Mol Genet 1997; 6: 229-236.
100. Burglen L, Seroz T, Miniou P et al. The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease. Am J Hum Genet 1997; 60: 72-79.
101. Roy N, Mahadevan MS, McLean M et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995; 80: 167-178.
102. Scharf JM, Endrizzi MG, Wetter A et al. Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics. Nat Genet 1998; 20: 83-86.
103. Deimling F von, Scharf JM, Liehr T et al. Human and mouse RAD17 genes: identification, localization, genomic structure and histological expression pattern in normal testis and seminoma. Hum Genet 1999; 105: 17-27.