Weng Wen-Chin, Skopova Vaclava, Baresova Veronika, Liu Yao-Lin, Hsueh Hsueh-Wen, Chien Yin-Hsiu, Hwu Wuh-Liang, Souckova Olga, Hnizda Ales, Kmoch Stanislav, Lee Ni-Chung, Zikanova Marie
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan.
Eur J Hum Genet. 2025 Jul;33(7):870-877. doi: 10.1038/s41431-024-01752-2. Epub 2024 Nov 27.
De novo synthesis of purines (DNPS) is a biochemical pathway that provides the purine bases for synthesis of essential biomolecules such as nucleic acids, energy transfer molecules, signaling molecules and various cofactors. Inborn errors of DNPS enzymes present with a wide spectrum of neurodevelopmental and neuromuscular abnormalities and accumulation of characteristic metabolic intermediates of the DNPS in body fluids and tissues. In this study, we present the second case of PAICS deficiency due to bi-allelic variants of PAICS gene encoding for a missense p.Ser179Pro and truncated p.Arg403Ter forms of the PAICS proteins. Two affected individuals were born at term after an uncomplicated pregnancy and delivery and presented later in life with progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Plasma and urinary concentrations of dephosphorylated substrates of PAICS, AIr and CAIr were elevated, though they remained undetectable in skin fibroblasts. Both variants affect structural domains in SAICARs catalytic site and the oligomerization interface. In silico modeling predicted negative effects on PAICS oligomerization, enzyme stability and enzymatic activity. Consistent with these findings, affected skin fibroblasts were devoid of PAICS protein and enzyme activity. This was accompanied by alterations in contents of other DNPS proteins, which had co-localized in granular structures that are characteristic of purinosome formation. Our observation expands the clinical spectrum of PAICS deficiency from recurrent abortions and fatal neonatal form to later onset neurodevelopmental disorders. The rarity of this condition may be based on poor clinical recognition and limited access to specialized laboratory tests diagnostic for PAICS deficiency.
嘌呤从头合成（DNPS）是一条生化途径，为核酸、能量传递分子、信号分子和各种辅因子等必需生物分子的合成提供嘌呤碱基。DNPS酶的先天性缺陷表现为广泛的神经发育和神经肌肉异常，以及DNPS特征性代谢中间体在体液和组织中的蓄积。在本研究中，我们报告了第二例PAICS缺乏症病例，该病例是由于PAICS基因的双等位基因变异导致的，该基因编码错义p.Ser179Pro和截短的p.Arg403Ter形式的PAICS蛋白。两名受影响个体足月出生，孕期和分娩过程均无并发症，出生后出现进行性脑萎缩、癫痫性脑病、精神运动发育迟缓及视网膜病变。PAICS的去磷酸化底物AIr和CAIr的血浆和尿液浓度升高，尽管在皮肤成纤维细胞中未检测到。这两种变异均影响SAICARs催化位点和寡聚化界面的结构域。计算机模拟预测对PAICS寡聚化、酶稳定性和酶活性有负面影响。与这些发现一致，受影响的皮肤成纤维细胞缺乏PAICS蛋白和酶活性。这伴随着其他DNPS蛋白含量的改变，这些蛋白共定位于嘌呤体形成特征性的颗粒结构中。我们的观察将PAICS缺乏症的临床谱从反复流产和致命的新生儿形式扩展到迟发性神经发育障碍。这种疾病的罕见性可能是由于临床认识不足以及获得PAICS缺乏症诊断专用实验室检测的机会有限。
