Eslamiyeh Hosein, Sefid Fatemeh, Iravani Farzaneh
Department of Pediatrics, Shahid Sadoughi University of Medical Science, Yazd, Iran.
Department of Medical Genetics, Shahid Sadoughi University of Medical Science, Yazd, Iran.
Mol Syndromol. 2025 Aug;16(4):335-341. doi: 10.1159/000542176. Epub 2024 Nov 29.
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.
蝶呤还原酶缺乏症（SRD）是一种非常罕见的精神运动障碍，与四氢生物蝶呤（BH4）合成过程中的酶缺陷有关，症状多样。其中最常见的是发育迟缓与肌张力减退。为阐明SRD的遗传病因，对该患者进行了全外显子组测序（WES），随后进行突变分析。
由儿科神经科医生进行全面的临床检查。进行了脑成像及全面的神经代谢检查，同时进行了生化检测，包括用高效液相色谱法（HPLC）定量测定脑脊液（CSF）蝶呤的浓度。提取基因组DNA并通过WES进行评估。随后对突变的蝶呤还原酶（SPR）蛋白结构进行生物信息学分析，并鉴定功能性蛋白氨基酸。
用HPLC对CSF的生物胺进行生化分析显示，高香草酸和5-羟吲哚乙酸水平极低，提示神经递质代谢紊乱。WES分析显示SPR基因外显子3存在纯合非同义变异（C.655C>T，p.Arg219Ter）。利用MOE软件生成了具有4HWK PDB编码的SPR蛋白结构分子图，与瑞士模型同源建模服务器预测的P.Arg219突变蛋白进行比较，使用COFACTOR软件确定配体结合位点残基，结果表明（R219）突变从第219位破坏了配体结合位点。另一个包括254和256位的重要密码子被遗漏。
全外显子组测序和生物信息学分析可以克服具有挑战性的神经发育病例漫长、昂贵且令人焦虑的诊断过程，从而改善管理并预防不可逆的副作用。
