Sharkia Rajech, Vuillaume Marie-Laure, Jain Sahil, Mahajnah Muhammad, Stoeva Radka, Guichet Agnès, Colin Estelle, Champ Jérome, Derive Nicolas, Chefdor Arnaud, Zalan Abdelnaser
Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qari 3007500, Israel.
Unit of Natural Sciences, Beit-Berl Academic College, Beit-Berl 4490500, Israel.
Genes (Basel). 2024 Nov 25;15(12):1508. doi: 10.3390/genes15121508.
BACKGROUND/OBJECTIVES: Biallelic mutations in the gene are associated with a rare genetic disease known as infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). In this study, we describe a new case carrying a previously identified mutation, provide an updated analysis of the relative frequencies of the clinical features across all published cases (including the three latest studies), and perform a bioinformatics analysis of the newly identified PTRH2 protein variants from a structural perspective.
Clinical examination of the patients was carried out, and genetic testing was performed using a genome sequencing strategy. A bioinformatics analysis was carried out for the newly reported mutations using PYMOL that was utilized to view the structure and analyze the mutations. Additionally, the ThermoMPNN webserver was employed to check the effect of point mutations on the overall stability of the protein.
Our findings indicate that motor delay, neuropathy, intellectual disability, distal weakness, hearing impairment, and ataxia are the most common symptoms, while the other clinical features fall into two frequency categories: moderately common ones and the least common ones. The bioinformatics analysis revealed that the Q85 residue is highly conserved, suggesting that mutations at this position could disrupt key signaling pathways or cellular functions. Indeed, the Q85R mutation was shown to significantly impair the stability and functionality of the protein.
The clinical presentation of IMNEPD remains highly variable in terms of both severity and progression. Mutations at the Q85 residue have been identified in nearly 50% of reported cases, highlighting this position as a potential mutational hotspot in the PTRH2 protein.
背景/目的：该基因的双等位基因突变与一种罕见的遗传性疾病相关，即婴儿期起病的多系统神经、内分泌和胰腺疾病（IMNEPD）。在本研究中，我们描述了一例携带先前已鉴定突变的新病例，对所有已发表病例（包括三项最新研究）的临床特征相对频率进行了更新分析，并从结构角度对新鉴定的PTRH2蛋白变体进行了生物信息学分析。
对患者进行了临床检查，并采用基因组测序策略进行了基因检测。使用PYMOL对新报道的突变进行了生物信息学分析，PYMOL用于查看结构和分析突变。此外，还使用了ThermoMPNN网络服务器来检查点突变对蛋白质整体稳定性的影响。
我们的研究结果表明，运动发育迟缓、神经病变、智力障碍、远端肌无力、听力障碍和共济失调是最常见的症状，而其他临床特征分为两个频率类别：中度常见和最不常见。生物信息学分析显示，Q85残基高度保守，表明该位置的突变可能会破坏关键信号通路或细胞功能。事实上，Q85R突变被证明会显著损害蛋白质的稳定性和功能。
IMNEPD的临床表现无论在严重程度还是进展方面都仍然高度可变。在近50%的报道病例中发现了Q85残基的突变，突出了该位置作为PTRH2蛋白潜在突变热点的地位。
