Adda Neggaz Leila, Dahmani Amira Chahinez, Derriche Ibtissem, Adda Neggaz Nawel, Boudjema Abdallah
Laboratory of Molecular and Cellular Genetics (LGMC), University of Sciences and Technology of Oran Mohamed Boudiaf, Oran, Algeria.
Biology Department, Faculty of Natural and Life Sciences, University of Mostaganem, Mostaganem, Algeria.
BMC Genom Data. 2025 May 15;26(1):35. doi: 10.1186/s12863-025-01325-2.
Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, which encodes cystinosin, a lysosomal cystine transporter. These mutations disrupt cystine efflux, leading to its accumulation in lysosomes and subsequent cellular damage. While more than 140 mutations have been identified, the functional and structural impacts of many nonsynonymous single nucleotide polymorphisms (nsSNPs) remain poorly understood. Nonsynonymous SNPs are of particular interest because they can directly alter protein structure and function, potentially leading to disease. Clinically, cystinosis most often presents with renal Fanconi syndrome, photophobia and vision loss due to corneal cystine crystals, and progressive neuromuscular complications such as distal myopathy and swallowing difficulties This study aimed to identify deleterious nsSNPs in the CTNS gene and evaluate their effects on cystinosin stability, structure, and function via computational tools and molecular dynamics simulations.
From a dataset of 12,028 SNPs, 327 nsSNPs were identified, among which 19 were consistently classified as deleterious across multiple predictive tools, including SIFT, PolyPhen, and molecular dynamics simulations. Stability predictions revealed that most of these mutations destabilize cystinosin, with G308R and G308V located in the sixth transmembrane domain essential for transporter function having the most severe effects. Molecular dynamics simulations revealed that these mutations significantly increase local flexibility, alter hydrogen bonding patterns, and enhance solvent accessibility, resulting in structural perturbations. Notably, D305G and F142S disrupted the transmembrane domains essential for the function of cystinosin, whereas compared with the wild-type protein, G309V resulted in increased stability. Conservation analysis revealed that 16 of the 19 mutations affected highly conserved residues, indicating their crucial roles in the function of cystinosin. Additionally, protein interaction analyses suggested that mutations could impact associations with lysosomal and membrane transport proteins.
This study identified 19 deleterious nsSNPs in the CTNS gene that impair cystinosin stability and function. These findings highlight the structural and functional importance of key residues, such as G308, D305, and F142, which play critical roles in maintaining the active conformation and transport capacity of cystinosin. These insights provide a foundation for future experimental validation and the development of targeted therapeutic strategies to mitigate the effects of pathogenic mutations in cystinosis.
胱氨酸病是一种罕见的常染色体隐性溶酶体贮积症，由CTNS基因突变引起，该基因编码溶酶体胱氨酸转运体胱氨酸转运蛋白。这些突变破坏了胱氨酸的外流，导致其在溶酶体中积累并随后造成细胞损伤。虽然已鉴定出140多种突变，但许多非同义单核苷酸多态性（nsSNPs）的功能和结构影响仍知之甚少。非同义SNP特别令人关注，因为它们可直接改变蛋白质结构和功能，可能导致疾病。临床上，胱氨酸病最常表现为肾性范科尼综合征、由于角膜胱氨酸晶体导致的畏光和视力丧失，以及进行性神经肌肉并发症，如远端肌病和吞咽困难。本研究旨在通过计算工具和分子动力学模拟，鉴定CTNS基因中的有害nsSNPs，并评估它们对胱氨酸转运蛋白稳定性、结构和功能的影响。
在12,028个SNP数据集中，鉴定出327个nsSNPs，其中19个在包括SIFT、PolyPhen和分子动力学模拟在内的多种预测工具中均被一致分类为有害。稳定性预测表明，这些突变大多会使胱氨酸转运蛋白不稳定，位于对转运体功能至关重要的第六跨膜结构域中的G308R和G308V影响最为严重。分子动力学模拟表明，这些突变显著增加了局部灵活性，改变了氢键模式，并增强了溶剂可及性，从而导致结构扰动。值得注意的是，D305G和F142S破坏了胱氨酸转运蛋白功能所必需的跨膜结构域，而与野生型蛋白相比，G309V导致稳定性增加。保守性分析表明，19个突变中有16个影响高度保守的残基，表明它们在胱氨酸转运蛋白功能中起关键作用。此外，蛋白质相互作用分析表明，突变可能影响与溶酶体和膜转运蛋白的关联。
本研究在CTNS基因中鉴定出19个有害的nsSNPs，它们损害了胱氨酸转运蛋白的稳定性和功能。这些发现突出了关键残基如G308、D305和F142的结构和功能重要性，它们在维持胱氨酸转运蛋白的活性构象和转运能力方面发挥着关键作用。这些见解为未来的实验验证以及开发有针对性的治疗策略以减轻胱氨酸病中致病突变的影响奠定了基础。
