title: Molecular analysis and prenatal diagnosis of human fumarase deficiency.
abstract: Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.
authors.affiliation: Amino Acid Disorder Laboratory, Massachusetts General Hospital, Boston 02129, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Coughlin
authors.forename: E
authors.initials: E
authors.lastname: Christensen
authors.forename: P L
authors.initials: PL
authors.lastname: Kunz
authors.forename: K S
authors.initials: KS
authors.lastname: Krishnamoorthy
authors.forename: V
authors.initials: V
authors.lastname: Walker
authors.forename: N R
authors.initials: NR
authors.lastname: Dennis
authors.forename: R A
authors.initials: RA
authors.lastname: Chalmers
authors.forename: O N
authors.initials: ON
authors.lastname: Elpeleg
authors.forename: D
authors.initials: D
authors.lastname: Whelan
authors.forename: R J
authors.initials: RJ
authors.lastname: Pollitt
authors.forename: V
authors.initials: V
authors.lastname: Ramesh
authors.forename: R
authors.initials: R
authors.lastname: Mandell
authors.forename: V E
authors.initials: VE
authors.lastname: Shih
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000096:biosynthesis; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011296:Prenatal Diagnosis / Q000379:methods; D051381:Rats; D017384:Sequence Deletion
chemical_list: D018076:DNA, Complementary; D005649:Fumarate Hydratase