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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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Abstract

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 SMN1–SMN2 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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Acknowledgments

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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Authors and Affiliations

  1. Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Sant Antoni Ma. Claret 167, 08025, Barcelona, Spain

    Laura Alías, Sara Bernal, María Jesus Barceló, Eva Also, Rebeca Martínez-Hernández, Montserrat Baiget & Eduardo F. Tizzano

  2. Centro de Investigación Bíomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain

    Laura Alías, Sara Bernal, María Jesus Barceló, Eva Also, Rebeca Martínez-Hernández, Montserrat Baiget & Eduardo F. Tizzano

  3. Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Pablo Fuentes-Prior

  4. Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain

    Francisco J. Rodríguez-Alvarez, Yolanda Martín & Concepción Hernández-Chico

  5. CIBERER, Madrid, Spain

    Francisco J. Rodríguez-Alvarez, Yolanda Martín & Concepción Hernández-Chico

  6. Unidad de Genética, Hospital La Fe, Valencia, Spain

    Elena Aller, Elena Grau & José M. Millán

  7. CIBERER, Valencia, Spain

    Elena Aller, Elena Grau & José M. Millán

  8. Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Hospital Virgen del Rocío, Sevilla, Spain

    Ana Peciña, Guillermo Antiñolo & Salud Borrego

  9. CIBERER, Sevilla, Spain

    Ana Peciña, Guillermo Antiñolo & Salud Borrego

  10. Genética Clínica, Hospital Materno Infantil, Badajoz, Spain

    Enrique Galán

  11. Laboratorio de Genética y Biología Molecular, Sanatorio Allende y Laboratorio de Biología Celular y Molecular, Fundación Allende, Córdoba, Argentina

    Alberto L. Rosa

  12. Laboratorio Biología Molecular, Hospital de Mérida, Mérida, Spain

    Miguel Fernández-Burriel

Authors
  1. Laura Alías
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  2. Sara Bernal
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  3. Pablo Fuentes-Prior
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  4. María Jesus Barceló
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  5. Eva Also
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  6. Rebeca Martínez-Hernández
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  7. Francisco J. Rodríguez-Alvarez
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  8. Yolanda Martín
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  9. Elena Aller
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  10. Elena Grau
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  11. Ana Peciña
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  12. Guillermo Antiñolo
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  13. Enrique Galán
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  14. Alberto L. Rosa
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  15. Miguel Fernández-Burriel
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  16. Salud Borrego
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  17. José M. Millán
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  18. Concepción Hernández-Chico
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  19. Montserrat Baiget
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  20. Eduardo F. Tizzano
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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). https://doi.org/10.1007/s00439-008-0598-1

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