Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH.

Abstract

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.

• Authors: Ranad Shaheen, Zuhair Rahbeeni, Amal Alhashem, Eissa Faqeih, Qi Zhao, Yong Xiong, Agaadir Almoisheer, Sarah M Al-Qattan, Halima A Almadani, Noufa Al-Onazi, Badi S Al-Baqawi, Mohammad Ali Saleh, Fowzan S Alkuraya
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 94 Issue 6 Pg. 898-904 (Jun 05 2014) ISSN: 1537-6605 [Electronic] United States
• PMID: 24836451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Serine
• Phosphoglycerate Dehydrogenase

Topics

• Abnormalities, Multiple (genetics)
• Alleles
• Amino Acid Sequence
• Animals
• Brain Diseases (genetics)
• Carbohydrate Metabolism, Inborn Errors (genetics)
• Chromosomes, Human, Pair 1 (genetics)
• Consanguinity
• Female
• Fetal Growth Retardation (genetics)
• Genetic Loci
• Homozygote
• Humans
• Ichthyosis (genetics)
• Infant
• Limb Deformities, Congenital (genetics)
• Magnetic Resonance Imaging
• Mice
• Microcephaly (genetics)
• Molecular Sequence Data
• Mutation
• Pedigree
• Phenotype
• Phosphoglycerate Dehydrogenase (deficiency, genetics, metabolism)
• Protein Conformation
• Psychomotor Disorders (genetics)
• Rare Diseases (genetics)
• Seizures (genetics)
• Serine (deficiency, metabolism)
• Ultrasonography, Prenatal