Unit of Human Biology and Genetics, Triangle Regional Research and Development Center, Kfar Qari 30075, Israel.
Unit of Natural Sciences, Beit-Berl Academic College, Beit-Berl 4490500, Israel.
Genes (Basel). 2023 Apr 30;14(5):1031. doi: 10.3390/genes14051031.
Peptidyl-tRNA hydrolase 2 (PTRH2) is an evolutionarily highly conserved mitochondrial protein. The biallelic mutations in the gene have been suggested to cause a rare autosomal recessive disorder characterized by an infantile-onset multisystem neurologic endocrine and pancreatic disease (IMNEPD). Patients with IMNEPD present varying clinical manifestations, including global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, sensorineural hearing loss, and abnormalities of thyroid, pancreas, and liver. In the current study, we conducted an extensive literature review with an emphasis on the variable clinical spectrum and genotypes in patients. Additionally, we reported on a new case with a previously documented mutation. A bioinformatics analysis of the various gene variants was also carried out from a structural perspective. It appears that the most common clinical characteristics among all patients include motor delay (92%), neuropathy (90%), distal weakness (86.4%), intellectual disability (84%), hearing impairment (80%), ataxia (79%), and deformity of head and face (70%). The less common characteristics include hand deformity (64%), cerebellar atrophy/hypoplasia (47%), and pancreatic abnormality (35%), while the least common appear to be diabetes mellitus (30%), liver abnormality (~22%), and hypothyroidism (16%). Three missense mutations were revealed in the gene, the most common one being Q85P, which was shared by four different Arab communities and was presented in our new case. Moreover, four different nonsense mutations in the gene were detected. It may be concluded that disease severity depends on the gene variant, as most of the clinical features are manifested by nonsense mutations, while only the common features are presented by missense mutations. A bioinformatics analysis of the various gene variants also suggested the mutations to be deleterious, as they seem to disrupt the structural confirmation of the enzyme, leading to loss of stability and functionality.
肽基-tRNA 水解酶 2（PTRH2）是一种进化上高度保守的线粒体蛋白。该基因的双等位基因突变已被认为导致一种罕见的常染色体隐性遗传疾病，其特征是婴儿期起病的多系统神经内分泌和胰腺疾病（IMNEPD）。患有 IMNEPD 的患者表现出不同的临床表现，包括伴有小头畸形的全面发育迟缓、生长迟缓、进行性共济失调、远端肌肉无力伴踝关节挛缩、脱髓鞘感觉运动神经病、感觉神经性听力损失以及甲状腺、胰腺和肝脏异常。在本研究中，我们进行了广泛的文献回顾，重点关注患者的可变临床谱和基因型。此外，我们还报告了一个新病例，该病例存在先前记录的突变。还从结构角度对各种 PTRH2 基因变异进行了生物信息学分析。似乎所有患者中最常见的临床特征包括运动延迟（92%）、神经病（90%）、远端无力（86.4%）、智力障碍（84%）、听力障碍（80%）、共济失调（79%）和头面部畸形（70%）。不太常见的特征包括手畸形（64%）、小脑萎缩/发育不良（47%）和胰腺异常（35%），而最不常见的似乎是糖尿病（30%）、肝脏异常（~22%）和甲状腺功能减退（16%）。在 PTRH2 基因中发现了三个错义突变，最常见的是 Q85P，它存在于四个不同的阿拉伯社区，也出现在我们的新病例中。此外，还检测到 PTRH2 基因中的四个不同的无义突变。可以得出结论，疾病严重程度取决于 PTRH2 基因变异，因为大多数临床特征是由无义突变引起的，而只有错义突变才会引起常见特征。对各种 PTRH2 基因变异的生物信息学分析也表明这些突变是有害的，因为它们似乎破坏了酶的结构稳定性，导致稳定性和功能丧失。
