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

3-phosphoglycerate dehydrogenase (PHGDH) deficiency is a disorder of L-seri ne biosynthesis that is characterized by congenital microcephaly, psychomot or retardation, and seizures. To investigate the molecular basis for this d isorder, the PHGDH mRNA sequence was characterized, and six patients from f our families were analyzed for sequence variations. Five patients from thre e different families were homozygous for a single nucleotide substitution p redicted to change valine at position 490 to methionine. The sixth patient was homozygous for a valine to methionine substitution at position 425; bot h mutations are located in the carboxyterminal part of PHGDH. In vitro expr ession 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 neurologic al impairment in our patients, the data presented in this paper suggest an important role for PHGDH activity and L-serine biosynthesis in the metaboli sm, development, and function of the central nervous system.