PSAT1 – Phosphoserine Aminotransferase Deficiency

Phosphoserine aminotransferase deficiency (PSATD; MONDO:0012596) is a rare autosomal recessive serine biosynthesis disorder resulting from biallelic variants in PSAT1 (HGNC:19129). Affected infants present with congenital microcephaly, psychomotor retardation, hypertonia, intractable seizures, and failure to thrive; biochemical hallmark is markedly reduced plasma and cerebrospinal fluid serine levels.

Genetic evidence includes compound heterozygous or homozygous PSAT1 variants identified in three probands from two unrelated families—two siblings with a frameshift and p.Asp100Ala variant (PMID:17436247) and an unrelated child with p.Ala15Pro and p.Gly79Arg missense variants (PMID:38546032). Segregation in the sibling pair confirms variant co-segregation with disease (1 affected relative). The inheritance pattern is autosomal recessive, with both missense and loss-of-function alleles observed.

Variant spectrum encompasses at least 2 missense (e.g., c.43G>C (p.Ala15Pro) [PMID:38546032]), 1 nonsense, 1 frameshift (e.g., c.299A>C (p.Asp100Ala) [PMID:17436247]), and splice-site changes. No recurrent founder mutations have been reported, and allele frequencies are absent or extremely rare in population databases.

Functional assays demonstrate pathogenicity: expression of p.Asp100Ala in patient fibroblasts yielded only 15% of wild-type V_max (PMID:17436247). Yeast-based complementation of human PSAT1 variants shows concordance with clinical severity across >199 alleles (PMID:32077105). Recombinant enzyme studies further reveal diverse mechanisms of dysfunction, including altered cofactor binding, thermostability, and catalytic efficiency (PMID:37627284). Early supplementation with L-serine and glycine partially rescues phenotype in one sibling, supporting haploinsufficiency as the disease mechanism.

There are no reported conflicting data disputing the association. All studies consistently link biallelic PSAT1 dysfunction to serine deficiency and neurological phenotypes.

Taken together, robust genetic and experimental evidence establishes an autosomal recessive association between PSAT1 and PSAT deficiency. Clinical genetic testing for PSAT1 variants enables early diagnosis and intervention with serine supplementation to improve neurodevelopmental outcomes.

References

• American Journal of Human Genetics • 2007 • Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. PMID:17436247
• Molecular Genetics & Genomic Medicine • 2024 • Phosphoserine aminotransferase deficiency diagnosed by whole-exome sequencing and LC-MS/MS reanalysis: A case report and review of literature. PMID:38546032
• Journal of inherited metabolic disease • 2020 • A yeast-based complementation assay elucidates the functional impact of 200 missense variants in human PSAT1. PMID:32077105
• Biomolecules • 2023 • Phosphoserine Aminotransferase Pathogenetic Variants in Serine Deficiency Disorders: A Functional Characterization. PMID:37627284

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