Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Am J Hum Genet. 2014 Sep 4;95(3):285-93. doi: 10.1016/j.ajhg.2014.07.012. Epub 2014 Aug 21.

Abstract

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Amino Acid Sequence
  • Brain Diseases / genetics*
  • Brain Diseases / metabolism
  • Consanguinity
  • Family
  • Female
  • Fetal Growth Retardation / genetics*
  • Fetal Growth Retardation / metabolism
  • Homozygote
  • Humans
  • Ichthyosis / genetics*
  • Ichthyosis / metabolism
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / metabolism
  • Male
  • Microcephaly / genetics*
  • Microcephaly / metabolism
  • Molecular Sequence Data
  • Mutation / genetics*
  • Phosphoglycerate Dehydrogenase / chemistry
  • Phosphoglycerate Dehydrogenase / deficiency
  • Phosphoglycerate Dehydrogenase / genetics*
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / genetics*
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Serine / biosynthesis*
  • Serine / chemistry
  • Transaminases / chemistry
  • Transaminases / deficiency
  • Transaminases / genetics*

Substances

  • Serine
  • Phosphoglycerate Dehydrogenase
  • Transaminases
  • phosphoserine aminotransferase
  • Phosphoric Monoester Hydrolases
  • phosphoserine phosphatase

Supplementary concepts

  • Neu Laxova syndrome