Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency - A neurometabolic disorder associated with reduced L-serine biosynthesis

Research output: Contribution to journalArticle


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.


  • Leo W.J. Klomp
  • Tom J. De Koning
  • Helga E.M. Malingré
  • Ellen A.C.M. Van Beurden
  • Miny Brink
  • Frans L. Opdam
  • Marinus Duran
  • Jaak Jaeken
  • Merce Pineda
  • Lionel Van Maldergem
  • Bwee Tien Poll-The
  • Inge E.T. Van den Berg
  • Ruud Berger
External organisations
  • University Medical Center Utrecht
  • Catholic University of Leuven
  • Hospital Sant Joan de Déu Barcelona
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical and Health Sciences
Original languageEnglish
Pages (from-to)1389-1399
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 2000 Jan 1
Publication categoryResearch
Externally publishedYes