Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency

Abstract

Neu-Laxova syndrome (NLS) is a term that unifies the independent reports by Neu and Laxova of a lethal multiple congenital anomaly syndrome (1). The main features of NLS involve defective somatic growth and the disturbed development of the central nervous system and skin, as well as many other anomalies that might present primarily as malformations or a malformation sequence (1). In 2014, mutations in PHGDH, which encodes phosphoglycerate dehydrogenase (PHGDH), were found in autosomal recessive cases of NLS (1). In addition, mutations in PSAT1, which encodes phosphoserine aminotransferase 1, and PSPH, which encodes phosphoserine phosphatase, were identified in several autosomal recessive cases of NLS (2). NLS is a genetically heterogeneous disorder that can be caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH (Fig. 1). l-Serine is a nonessential amino acid that is synthesized de novo from the glycolytic intermediate 3-phosphoglycerate through three steps that are respectively catalyzed by PHGDH, phosphoserine aminotransferase, and phosphoserine phosphatase (3). PHGDH deficiency, which is a congenital error of serine metabolism, was first described in 1996, before NLS was proposed as a syndrome (4). PHGDH is the first enzyme in the de novo biosynthesis of serine from carbohydrates. A reduced ability to synthesize l-serine has potentially serious consequences for cellular metabolism (5). Serine is Abstract Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH. l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tapestripped stratum corneum of the NLS patient's skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient's stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.-Takeichi, T.

The efficacy of synthetic pseudo‐ceramide for dry and rough lips

“…Three continuous SC tape strips (2.5 × 3.5 cm) were obtained from each lip site by making them evenly adhere with a finger for several seconds and then stripping an adhesive acrylic film (465#40; Teraoka Seisakusho, Tokyo, Japan). The samples were subjected to LC/MS analysis to assess the levels of 11 major ceramide species [5,15]. The tape strips were cut into two equal half‐strips: one half was used for ceramide measurement and the other half was used for quantifying protein.…”

Microcephaly in Neurometabolic Diseases

“…Neu–Laxova syndrome (NLS) is a lethal syndrome of intrauterine growth retardation and multiple malformations. The condition is most likely caused by mutations in the PHGDH, PSAT1, or PSPH genes, which are associated with the serine synthesis pathway [ 10 , 11 ]. Neu–Laxova syndrome type 1 is a more severe phenotypic variant of 3-PGDH deficiency.…”

“…The mutation in the PHGDH gene (locus 1p12) occurs. Most PHGDH mutations that cause NLS are missense mutations, although nonsense, splicing or frame shift mutations have also been reported [ 11 ]. Acuna-Hidalgo et al, (2014) reported close parental consanguinity in few investigated families [ 10 ].…”

Acylceramide is a key player in skin barrier function: insight into the molecular mechanisms of skin barrier formation and ichthyosis pathogenesis

“…Mutations in PHGDH , PSAT1 , and PSPH cause Neu–Laxova syndrome (NLS), which produces severe congenital anomalies in the central nervous system and diffuse erythematous skin lesions with scaling over the entire body [24]. An NLS patient with PHGDH deficiency demonstrated a significant reduction in 11 major classes of ceramides, including CerEOS, in the stratum corneum [24]. Thus, l ‐serine shortage caused by reduced activity of PHGDH is considered to lead to the ceramide reduction seen in the epidermis of NLS patients.…”

“…The other route of ceramide synthesis is a pathway using long‐chain bases which are produced de novo [23]. l ‐serine, a nonessential amino acid, is necessary for the de novo synthesis of long‐chain bases [24]. l ‐serine is made de novo from 3‐phosphoglycerate, a glycolytic intermediate, via three sequential reactions catalyzed in turn by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) [25].…”