title: Evidence of common ancestry for the maple syrup urine disease (MSUD) Y438N allele in non-Mennonite MSUD patients.
abstract: Maple syrup urine disease (MSUD) is a rare (1/185,000) autosomal recessive inborn error of branched-chain amino acid metabolism characterized by increased plasma leucine, isoleucine, and valine levels. Though, genetically heterogeneous in the worldwide population, MSUD in Old Order Mennonites (1/150-176) is the result of a tyrosine to asparagine substitution (Y438N; previously Y393N) in the E1alpha subunit of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex. Due to endogamous practices, the presence of Y438N in all reported Mennonite MSUD patients has historically been attributed to a founder effect. However, we have also identified the Y438N defect in eight MSUD patients of non-Mennonite lineage. To evaluate the genetic origin of this defect in these non-Mennonite patients, we examined Mennonite MSUD families and non-Mennonite MSUD families using microsatellite markers located on chromosome 19q13.1-13.2 (location of E1alpha gene, BCKDHA). Haplotype analyses revealed a major and four minor haplotypes that cosegregate with the Y438N allele in the Old Order Mennonite MSUD patients and carrier relatives. Analyses of eight non-Mennonite MSUD patients reveal that three of the non-Mennonite MSUD patients shared common Mennonite Y438N haplotypes, strongly suggesting Mennonite ancestry. However, the remaining non-Mennonite patients carry Y438N haplotypes that are significantly different from the Mennonite Y438N haplotype, suggesting that the occurrence of the defect in these families is due to either pre-Mennonite or de novo events.
authors.affiliation: Genetics Area Program, University of Missouri, M121 Medical Sciences Building, Columbia, MO 65212, USA.
authors.forename: Latisha D
authors.initials: LD
authors.lastname: Love-Gregory
authors.forename: Julia
authors.initials: J
authors.lastname: Grasela
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hillman
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Phillips
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000483:Alleles; D001483:Base Sequence; D019143:Evolution, Molecular; D005260:Female; D018703:Founder Effect; D006801:Humans; D007658:Ketone Oxidoreductases / Q000235:genetics*; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics*; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation
chemical_list: D009097:Multienzyme Complexes; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)