C.655C>T Variant of Sepiapterin Reductase Deficiency: Genetic and Bioinformatic Analysis

Sepiapterin reductase deficiency (SRD) is a very rare psychomotor disorder related to enzyme defects in synthesizing tetrahydrobiopterin (BH4) with a spectrum of symptoms. The most common of which are developmental delay and hypotonia. To elucidate the genetic cause of SRD, the patient was analyzed by whole-exome sequencing (WES) followed by mutation analysis.

A complete clinical examination was performed by a pediatric neurologist. Brain imaging and a thorough neuro-metabolic investigation were applied along with biochemical tests including high-performance liquid chromatography (HPLC) to quantify the concentrations of cerebrospinal fluid (CSF) pterins. Genomic DNA was extracted and evaluated through WES. This was followed by bioinformatic analysis of mutated sepiapterin reductase (SPR) protein structure and identification of the functional protein amino acids.

Biochemical analysis of biogenic amines of CSF with HPLC showed very low levels of homovanillic acid and 5-hydroxyindolacetic acid in favor of neurotransmitter metabolism disorder. WES analysis displayed a homozygous nonsynonymous variant in exon 3 of the SPR gene (C.655C>T, p.Arg219Ter). The molecular graphic of SPR protein structure with 4HWK PDB code was generated by MOE software in comparison with P.Arg219* mutated protein which is predicted by a Swiss model homology modeling server determining the ligand-binding site residues using COFACTOR software and indicated that the (R219*) mutation destroyed the ligand-binding site from the position of 219. Another important codon including 254 and 256 positions is omitted.

Whole exome sequencing and bioinformatic analysis could overcome lengthy, expensive, and emotional diagnostic adventures of challenging neurodevelopmental cases leading to improved management and prevention of irreversible side effects.