title: Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis.
abstract: 3-phosphoglycerate dehydrogenase (PHGDH) deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures. To investigate the molecular basis for this disorder, the PHGDH mRNA sequence was characterized, and six patients from four families were analyzed for sequence variations. Five patients from three different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine. The sixth patient was homozygous for a valine to methionine substitution at position 425; both mutations are located in the carboxyterminal part of PHGDH. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA-blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurological impairment in our patients, the data presented in this paper suggest an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.
authors.affiliation: Department of Metabolic Diseases, University Medical Center Utrecht, 3584 AE Utrecht, The Netherlands. L.Klomp@wkz.azu.nl
authors.forename: L W
authors.initials: LW
authors.lastname: Klomp
authors.forename: T J
authors.initials: TJ
authors.lastname: de Koning
authors.forename: H E
authors.initials: HE
authors.lastname: Malingré
authors.forename: E A
authors.initials: EA
authors.lastname: van Beurden
authors.forename: M
authors.initials: M
authors.lastname: Brink
authors.forename: F L
authors.initials: FL
authors.lastname: Opdam
authors.forename: M
authors.initials: M
authors.lastname: Duran
authors.forename: J
authors.initials: J
authors.lastname: Jaeken
authors.forename: M
authors.initials: M
authors.lastname: Pineda
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
authors.forename: I E
authors.initials: IE
authors.lastname: van den Berg
authors.forename: R
authors.initials: R
authors.lastname: Berger
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003001:Cloning, Molecular; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009018:Morocco; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D050543:Phosphoglycerate Dehydrogenase; D020161:Physical Chromosome Mapping; D012150:Polymorphism, Restriction Fragment Length; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016415:Sequence Alignment; D012694:Serine / Q000096:biosynthesis*; D014421:Turkey
chemical_list: D012333:RNA, Messenger; D012694:Serine; D002237:Carbohydrate Dehydrogenases; D050543:Phosphoglycerate Dehydrogenase