A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins

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.

Two Japanese Patients With SMA Type 1 Suggest that Axonal-SMN May Not Modify the Disease Severity

“…7 However, from our own observations, the clinical phenotype of the patients with the p.W92S mutation is not as severe as patient 1 in this study: neither of them required artificial ventilators in the first year of life. 11 In other words, disruption of the C-terminal domain of FL-SMN may have a more serious effect on SMA phenotype compared with a mutation in the Tudor domain of a-SMN (and FL-SMN).…”

“…11 The p.Try92Ser mutation alters a-SMN structure. 7 Locatelli et al clearly demonstrated that the p.W92S mutation hampers axonal growth of NSC34 motor neurons induced by a-SMN.…”

Fugu rubripes and human survival motor neuron genes: Structural and functional similarities in comparative genome studies

“…The tudor domain of SMN, is the essential binding site of SMN to spliceosomal proteins in assisting spliceosomal U small nuclear ribonucleoproteins (U snRNP) assembly and to mediate SMN-oligomerization (Selenko et al, 2001;Brenner et al, 2002;Sun et al, 2005). Mutations in the tudor domain have been shown to be associated with SMA phenotype (Lefebvre Cusco et al, 2004;Sun et al, 2005;Kotani et al, 2007). Gemin2 binding is essential for the formation of SMN complex.…”

Diagnosis of Spinal Muscular Atrophy Via High-Resolution Melting Analysis Symmetric Polymerase Chain Reaction Without Probe: A Screening Evaluation forSMN1Deletions and Intragenic Mutations

“…We previously reported a novel mutation in SMN1 exon 3, 275G > C. This mutation was identified in two patients with SMA type 1, and results in a tryptophan-to-serine substitution at amino acid 92 (W92S), which is found at the N-terminal of the SMN Tudor domain (Kotani et al, 2007).…”