Principal Investigator(s): Prof. Dr. med. Martin Zenker, Dr. rer. nat. Denny Schanze

Student(s): M. Sc. Fatima Abdelfattah (PhD student)

Description: Neu-Laxova syndrome (NLS1, MIM 256520; NLS2, MIM 610936) is a rare autosomal recessive congenital malformation disorder leading to perinatal lethality. The main clinical features include intrauterine growth restriction, microcephaly with variable brain malformations, ichthyosis, and limb malformations. Our group has contributed to the identification of mutations in three genes (PHGDH, PSAT1, PSPH) encoding enzymes of the serine biosynthesis pathway as the underlying cause of NLS. The known spectrum of NLS-associated mutations suggests that they probably do not lead to a complete loss of function, but residual enzyme activities have not been measured to date. Moreover, a less severe clinical phenotype of inborn errors of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures was previously associated with defects in the same metabolic pathway.

This project aims at the further delineation of genotypic and functional correlations of the phenotype in serine biosynthesis pathway disorders. To this end, we are collecting phenotype data of new cases with NLS and other serine pathway disorders and perform genetic analysis of the known genes. We are using patient cells and in vitro models expressing mutant enzyme proteins to quantify incapacitation of this metabolic pathway as a function of the nature of individual mutations.

In patients with NLS-like phenotypes but without mutations in the three genes known, so far, we are also searching for novel genetic causes by exome/genome sequencing.

Call for patients: This study is still recruiting cases with NLS, NLS-like phenotypes or milder forms of serine biosynthesis pathway disorders. Please contact the PIs of this study.

Legende: L-serine biosynthesis pathway (from Acuna-Hidalgo et al., Am J Hum Genet 2014)

Funding: Application in preparation

Publications: https://www.ncbi.nlm.nih.gov/pubmed/25152457