Abstract
Although most patients with spinal muscular atrophy (SMA) are homozygous for deletion of the SMN1 gene, some patients bear one SMN1 copy with a subtle mutation. Detection of such an intragenic mutation may be helpful not only in confirming diagnosis but also in elucidating functional domains of the SMN protein. In this study, we identified a novel mutation in SMN1 of two Japanese patients with type I SMA. DHPLC and sequencing analysis revealed that they harbored a point mutation in SMN1 exon 3, 275G > C, leading to tryptophan-to-serine substitution at amino acid 92 (W92S) at the Nterminal of SMN Tudor domain. In-vitro protein binding assays showed that the mutation severely reduced interaction of the domain with SmB protein and fibrillarin, suggesting that it impairs the critical function of SMN. In conclusion, we reported here that a novel mutation, W92S, in the Tudor domain affects the interaction of SMN with the target proteins.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Brahe C, Clermont O, Zappata S, Tiziano F, Melki J, Neri G (1996) Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I. Hum Mol Genet 5:1971-976
Bühler D, Raker V, Luhrmann R, Fischer U (1999) Essential role for the tudor domain of SMN in spliceosomal U snRNP assembly: implications for spinal muscular atrophy. Hum Mol Genet 8:2351-357
Bussaglia E, Clermont O, Tizzano E, Lefevbre S, Bürglen L, Cruaud C, Urtizberea JA, Colomer J, Munnich A, Baiget M, Melki J (1995) A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nature Genet 11:335-37
Clermont O, Burlet P, Cruad C, Bertrandy S, Melki J, Munnich A, Lefevbre S (1997) Mutation analysis of the SMN gene in undeleted SMA patients. Am J Hum Genet 61:A329
Cuscó I, Barcelo MJ, del Rio E, Baiget M, Tizzano EF (2004) Detection of novel mutations in the SMN Tudor domain in type I SMA patients. Neurology 63:146-49
Cuscó I, Lopez E, Soler-Botija C, Barcelo MJ, Baiget M, Tizzano EF (2003) A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene. Hum Mutat 22:136-43
Cuscó I, Barcelo MJ, Rojas-Garcia R, Illa I, Gamez J, Cervera C, Pou A, Izquierdo G, Baiget M, Tizzano EF (2006) SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings. J Neurol 253:21-5
DiDonato CJ, Morgan K, Carpten JD, Fuerst P, Ingraham SE, Prescott G, McPherson JD, Wirth B, Zerres K, Hurko O, Wasmuth JJ, Mendell JR, Burghes AHM, Simard LR (1994) Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy. Am J Hum Genet 55:1218-229
Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B (2002) 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 70:358-68
Gubitz AK, Feng W, Dreyfuss G (2004) The SMN complex. Exp Cell Res 296:51-6
Harada Y, Sutomo R, Sadewa AH, Akutsu T, Takeshima Y, Wada H, Matsuo M, Nishio H. (2002) Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. J Neurol 249:1211-219
Jones KW, Gorzynski K, Hales CM, Fischer U, Badbanchi F, Terns RM, Terns MP (2001) Direct interaction of the spinal mucular atrophy disease protein SMN with the small nucleolar RNA-associated protein fibrillarin. J Biol Chem 276:38645-8651
Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frezal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155-65
MacKenzie AE, Gendron NH. (2001) Tudor reign. Nat Struct Biol 8:13-5
Martin Y, Valero A, del Castillo E, Pascual SI, Hernandez-Chico C (2002) Genetic study of SMA patients without homozygous SMN1 deletions: identification of compound heterozygotes and characterisation of novel intragenic SMN1 mutations. Hum Genet 110:257-63
Melki J, Lefebvre S, Burglen L, et al. (1994) De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 264:1474-477
Mohaghegh P, Rodrigues NR, Owen N, Ponting CP, Le TT, Burghes AH, Davies KE. (1999) Analysis of mutations in the tudor domain of the survival motor neuron protein SMN. Eur J Hum Genet 7:519-25
Ponting CP (1997) Tudor domains in proteins that interact with RNA. Trends Biochem Sci 22:51-2
Roy N, Mahadevan MS, McLean M, et al. (1995) The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80:167-78
Selenko P, Sprangers R, Stier G, Buhler D, Fischer U, Sattler M (2001) SMN Tudor domain structure and its interaction with the Sm proteins. Nat Struct Biol 8:27-1
Sossi V, Giuli A, Vitali T, Tiziano F, Mirabella M, Antonelli A, Neri G, Brahe C (2001) Premature termination mutation in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype. Eur J Hum Genet 9:113-20
Sun Y, Grimmler M, Schwarzer V, Schoenen F, Fischer U, Wirth B (2005) Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum Mutat 25:64-1
van der Steege G, Grootscholten PM, van der Vlies P, Draaijers TG, Osinga J, Cobben JM, Scheffer H, Buys CH (1995) PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 345:985-86
Wang J, Dreyfuss G (2001) Characterization of functional domains of the SMN protein in vivo. J Biol Chem 276:45387-5393
Wirth B (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 15:228-37
Zerres K, Davies KE. (1999) 59th ENMC International Workshop: Spinal Muscular Atrophies: recent progress and revised diagnostic criteria (17-9 April 1998, Soestduinen, The Netherlands). Neuromuscul Disord 9(4):272-78
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kotani, T., Sutomo, R., Sasongko, T.H. et al. A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J Neurol 254, 624–630 (2007). https://doi.org/10.1007/s00415-006-0410-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-006-0410-x