title: Revisiting MSUD in Portuguese Gypsies: evidence for a founder mutation and for a mutational hotspot within the BCKDHA gene.
abstract: Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. In the context of the wide mutational spectrum known for this disease, a few common mutations have been described in populations where founder effects played a major role in modeling diversities. In Portugal, for instance, a high proportion of patients are of Gypsy origin and all share the same mutation (c.117delC-alpha; p.R40GfsX23), causing the neonatal severe form of MSUD. In this study, we used four microsatellite markers closely flanking the BCKDHA gene (E1alpha protein) to demonstrate that c.117delC-alpha is a founder mutation responsible for the high incidence of the disorder among Portuguese Gypsies. These results are of medical relevance since carrier tests and prenatal diagnosis can be offered to families at risk, particularly because the carrier frequency of c.117delC-alpha was estimated at 1.4% among the healthy Portuguese Gypsies from the South of the country. Finally we present evidence that the genomic region of the BCKDHA gene where c.117delC-alpha is located is likely a mutational hotspot, since recurrence of c.117delC-alpha was observed in two distinct population groups.
authors.affiliation: IPATIMUP- Institute of Pathology and Molecular Immunology of University of Porto, Porto, Portugal. mquental@ipatimup.pt
authors.forename: Sofia
authors.initials: S
authors.lastname: Quental
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gusmão
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: António
authors.initials: A
authors.lastname: Amorim
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Prata
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006579:Heterozygote; D006801:Humans; D008297:Male; D008375:Maple Syrup Urine Disease / Q000208:ethnology* / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D011174:Portugal / Q000208:ethnology; D006178:Romani People / Q000235:genetics*
chemical_list: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)