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

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.

Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain

“…In addition, the distribution of mutations for other diseases that are believed to have originated among the Basques is similar to that seen for R1441G. This includes the CAPN3 2362AG→TCATCT mutation for limb-girdle muscular dystrophy type 2A (estimated to have arisen in the sixth to eighth century) [35] and PRNP D178N which results in fatal familial insomnia [36]. …”

Somatic mosaicism in a case of apparently sporadic Creutzfeldt‐Jakob disease carrying a de novo D178N mutation in the PRNP gene

“…A fragment of 300 bp was amplified using primers MP‐L and MP‐H (Table I) followed by double restriction enzyme digestion, using enzymes Tth111I and HpyCH4IV (New England Biolabs, Ipswich, MA), as described elsewhere [Rodriguez‐Martinez et al, 2008].…”

“…To further characterize the genomic region surrounding the PRNP gene, four microsatellite loci (MsP1, MsP2, MsP4, and MsP5) [Rodriguez‐Martinez et al, 2005] and five single nucleotide polymorphisms (rs2756271, rs6037932, rs13045348, rs6116474, and rs6116475) [Rodriguez‐Martinez et al, 2008] were analyzed in the patient and the parents.…”

Neurogenetic Disorders in the Basque Population

“…A genealogic search through parochial registries up to the XVI century could not identify the probable common ancestor. Our findings suggest a limited number of mutational events in the PNRP gene, and that most Basque and Spanish cases, as well as some of the Italian ones (from the Tuscany region) are genetically related (Rodríguez‐Martínez et al., ). On the other hand, one apparently sporadic case carrying the same mutation and with a different haplotype was also detected in a non‐Basque patient living in the Basque Country (Alzualde et al., ).…”