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Molecular evidence of founder effects of fatal familial insomnia through SNP haplotypes around the D178N mutation

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Abstract

This work presents a detailed investigation of the genomic region surrounding the PRNP gene in a sample of patients diagnosed with fatal familial insomnia (FFI) from several European countries, notably Spain. The main focus of the study was to explore the origins of the chromosomes carrying the D178N mutation by designing a single-nucleotide polymorphism (SNP) haplotype around the PRNP gene. Haplotypes were constructed by genotyping six SNPs (rs2756271, rs13040327, rs6037932, rs13045348, rs6116474, and rs6116475) in 25 FFI patients from all over Spain. To augment the geographical scope of our study, 13 further FFI cases from Germany (9) and Italy (4) were also examined. Genotyping of SNPs in conjunction with the analysis of genealogical data for a group of FFI patients revealed the existence of two distinct haplotypes potentially associated with the D178N mutation. Of them, GCATTA-M proved to be the common haplotype of Spanish patients, whereas ACATTA-M was typical of the German cases. It is interesting to note that both haplotypes were identified in the Italian samples: GCATTA-M in a family from the Tuscany region and ACATTA-M in a family from the Veneto region. Our findings suggest the occurrence of two independent D178N-129M mutational events in Europe, preserved and transmitted from one generation to the next until nowadays. Likewise, results based on the analysis of SNP data indicate that previous hypotheses postulating that the D178N mutation had independent origins for each family and that its global distribution was determined by recurrent mutational events must be regarded with caution.

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Acknowledgments

The authors are grateful to Prof. P Montagna, P Cortelli, and Dr. P Avoni for providing the clinical data on the Italian case I-02. This study was funded by Research Projects EET-2002/05165 from Ministerio de Educación y Ciencia (Spain), GIU 05/51 from Universidad del País Vasco (UPV/EHU, Spain), and FIS 05/0912 from Fondo de Investigaciones Sanitarias (Spain). AB Rodríguez-Martínez was supported by a doctoral fellowship from the Basque Government (BFI02.1).

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Authors and Affiliations

  1. Departamento de Zoología y Biología Celular, Facultad de Farmacia, Universidad del País Vasco, 01006, Vitoria-Gasteiz, Alava, Spain

    Ana B. Rodríguez-Martínez & Marian M. de Pancorbo

  2. Departamento de Genética y Antropología Física, Facultad de Ciencia y Tecnología, Universidad del País Vasco, 48080, Bilbao, Biscay, Spain

    Miguel A. Alfonso-Sánchez & José A. Peña

  3. Alzheimer’s Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Institut d’Investigació Biomèdica August Pi i Sunyer, 08036, Barcelona, Spain

    Raquel Sánchez-Valle

  4. National TSE Reference Center, Department of Neurology, Georg-August University of Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    Inga Zerr

  5. Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy

    Sabina Capellari

  6. Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220, Madrid, Spain

    Miguel Calero

  7. Servicio de Neurología, Hospital de Cruces, Barakaldo, Biscay, Spain

    Juan J. Zarranz

  8. Servicio General de Investigación Genómica: Banco de ADN, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006, Vitoria-Gasteiz, Alava, Spain

    Marian M. de Pancorbo

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  1. Ana B. Rodríguez-Martínez
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  2. Miguel A. Alfonso-Sánchez
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  3. José A. Peña
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  4. Raquel Sánchez-Valle
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  5. Inga Zerr
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  6. Sabina Capellari
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  7. Miguel Calero
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  8. Juan J. Zarranz
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  9. Marian M. de Pancorbo
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Correspondence to Marian M. de Pancorbo.

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Table S1

Age of onset, sex, duration of illness, and clinical features of 38 European FFI cases (DOC 169 kb)

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Rodríguez-Martínez, A.B., Alfonso-Sánchez, M.A., Peña, J.A. et al. Molecular evidence of founder effects of fatal familial insomnia through SNP haplotypes around the D178N mutation. Neurogenetics 9, 109–118 (2008). https://doi.org/10.1007/s10048-008-0120-x

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