Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene

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Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II–III) predominated in males (p < 0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T>G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN–SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein.

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This work was supported by CIBERER (to L.A. and E. Aller), GENAME Project (to S. Bernal, R.M.H., F.J.M.A., E.G. and A.P.), and FIS05-2416 (to E. Also); Grants: FIS 05-2416 (E.F.T.) and GENAME Project (E.F.T., C·H.C., J.M.M., S. Borrego, J.C., M.R.) We wish to thank the consenting parents and patients who made this study possible. We are indebted to all the colleagues and laboratories that referred samples for this study, in particular to Drs. Jaume Colomer, Manel Roig, Jordi Rosell, Ricardo Rojas, Alfredo Santana and Carlos Vazquez. We are also indebted to Dr. Brunhilde Wirth for providing us anonymous samples of German patients with point mutations, to Dr. Ignasi Gich for helpful comments on data statistics analysis and to Silvia Alcover for technical assistance.

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Correspondence to Eduardo F. Tizzano.

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Alías, L., Bernal, S., Fuentes-Prior, P. et al. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum Genet 125, 29–39 (2009) doi:10.1007/s00439-008-0598-1

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  • Spinal Muscular Atrophy
  • Survival Motor Neuron
  • Spinal Muscular Atrophy Patient
  • SMN1 Gene
  • Spinal Muscular Atrophy Type