TY - JOUR
T1 - Evidence of common ancestry for the maple syrup urine disease (MSUD) Y438N allele in non-Mennonite MSUD patients
AU - Love-Gregory, Latisha D.
AU - Grasela, Julia
AU - Hillman, Richard E.
AU - Phillips, Charlotte L.
N1 - Funding Information:
We are greatly indebted to the patients and their families for their participation in this study. We sincerely thank Jonathan Dyer and Jessica Newton for technical assistance, Mary Nellis and Dean Danner of Emory University for providing additional samples, and Howard Wilson for his assistance with graphics. This work was supported in part by research grants from the Children’s Miracle Network of the University of Missouri School of Medicine, Columbia, Missouri, and the Leda J. Sears Trust Foundation.
Funding Information:
2Accession numbers and URLs for data in this article are as follows: Cooperative Human Linkage Center (CHLC), http://research.marshfieldclinic.org/genetics/; Duke University Center for Human Genetics, website supported by Grant NS26630 (Dr. Margaret Pericak-Vance), http://www2.mc.duke.edu/depts/medicine/ medgen/allele_freqs/; Genome Database, http://www.gdb.org (for D19S220 [Accession ID GDB:188391] and D19S200 allele set [Accession ID GDB:62907], D19S200 [Accession ID GDB:182272] and D19S200 allele set [Accession ID GDB:53546], D19S223 [Accession ID GDB:188482] and D19S223 allele set [Accession ID GDB:63015], D19S682 [Accession ID GDB:685095], D19S408 [Accession ID GDB:199406], and D19S408 allele set [Accession ID GDB:239690], D19S178 [Accession ID GDB:180707] and D19S178 allele set [Accession ID GDB:60674]).
PY - 2002
Y1 - 2002
N2 - 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 E1α subunit of the branched-chain α-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 E1α 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.
AB - 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 E1α subunit of the branched-chain α-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 E1α 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.
KW - Amino acidemias
KW - Haplotypes
KW - Maple syrup urine disease
KW - Metabolic disorder
UR - http://www.scopus.com/inward/record.url?scp=0036351290&partnerID=8YFLogxK
U2 - 10.1006/mgme.2001.3264
DO - 10.1006/mgme.2001.3264
M3 - Article
C2 - 11825067
AN - SCOPUS:0036351290
VL - 75
SP - 79
EP - 90
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 1
ER -