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

Takuya Takeichi,Yusuke Okuno,Akane Kawamoto,Takeshi Inoue,Eiko Nagamoto,Chiaki Murase,Eri Shimizu,Kenichi Tanaka,Yuichi Kageshita,Satoshi Fukushima,Michihiro Kono,Junko Ishikawa,Hironobu Ihn,Yoshiyuki Takahashi,Masashi Akiyama

doi:10.1194/jlr.p087536

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 tape-stripped 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.

Highlights

Neu-Laxova syndrome (NLS) is a term that unifies the independent reports by Neu and Laxova of a lethal multiple congenital anomaly syndrome [1]
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: phosphoglycerate dehydrogenase (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]
Severe phenotypes of NLS might be caused by truncation mutations rather than by missense mutations of PHGDH

Summary

Introduction

Neu-Laxova syndrome (NLS) is a term that unifies the independent reports by Neu and Laxova of a lethal multiple congenital anomaly syndrome [1]. 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]. Incorporated directly into proteins and is a precursor for the de novo biosynthesis of glycine, cysteine, and the nonstandard amino acid selenocysteine. It is essential for the biosynthesis of phosphatidylserine and sphingolipids [5]. The first step in the de novo pathway of ceramide synthesis is catalyzed by serine palmitoyl transferase, condensing l-serine and palmitoyl-CoA to generate 3-ketodihydrosphingosine (Fig. 1) [9]

Methods

Results

Conclusion