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

Klomp, Leo W.J. ; De Koning, Tom J. LU ; Malingré, Helga E.M. ; Van Beurden, Ellen A.C.M. ; Brink, Miny ; Opdam, Frans L. ; Duran, Marinus ; Jaeken, Jaak ; Pineda, Merce and Van Maldergem, Lionel , et al. (2000) In American Journal of Human Genetics 67(6). p.1389-1399
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Human Genetics
volume
67
issue
6
pages
11 pages
publisher
Cell Press
external identifiers
  • scopus:0033652293
  • pmid:11055895
ISSN
0002-9297
DOI
10.1086/316886
language
English
LU publication?
no
id
6eed9a8a-2e2f-4a72-a78c-7b92d490e7e2
date added to LUP
2020-03-03 19:16:01
date last changed
2024-04-03 02:29:53
@article{6eed9a8a-2e2f-4a72-a78c-7b92d490e7e2,
  abstract     = {{<p>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.</p>}},
  author       = {{Klomp, Leo W.J. and De Koning, Tom J. and Malingré, Helga E.M. and Van Beurden, Ellen A.C.M. and Brink, Miny and Opdam, Frans L. and Duran, Marinus and Jaeken, Jaak and Pineda, Merce and Van Maldergem, Lionel and Poll-The, Bwee Tien and Van den Berg, Inge E.T. and Berger, Ruud}},
  issn         = {{0002-9297}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{6}},
  pages        = {{1389--1399}},
  publisher    = {{Cell Press}},
  series       = {{American Journal of Human Genetics}},
  title        = {{Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency - A neurometabolic disorder associated with reduced L-serine biosynthesis}},
  url          = {{http://dx.doi.org/10.1086/316886}},
  doi          = {{10.1086/316886}},
  volume       = {{67}},
  year         = {{2000}},
}