The PHGDH gene encodes an enzyme that is essential for the synthesis of the L-serine amino acid. Using NAD+/NADH as a cofactor, PHGDH forms a homotetramer and catalyzes the first step in the serine biosynthesis pathway, the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate. As serine is essential for protein synthesis and is a precursor to compounds such as sphingomyelin, glycine, and cysteine, PHGDH deficiency can have strong pathological consequences.
Mutations in the PHGDH gene result in Neu-Laxova Syndrome 1 (NLS1), a severe and usually fatal disorder characterized by ichthyosis, microcephaly, intra-uterine growth retardation, nervous system abnormalities, limb deformities, edema, and facial dysmorphia. The gene is also associated with Phosphoglycerate Dehydrogenase Deficiency (PHGDHD), a less severe phenotype characterized by congenital microcephaly, psychomotor retardation, and seizures.