Nicolaou Paschalis, Tanteles George A, Votsi Christina, Zamba-Papanicolaou Eleni, Papacostas Savvas S, Christodoulou Kyproula, Christou Yiolanda-Panayiota
Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Front Genet. 2021 Nov 19;12:746101. doi: 10.3389/fgene.2021.746101. eCollection 2021.
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, prediction analysis and structural modeling of the identified variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two biallelic variants: the novel, p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His variant. Prediction analysis of the two variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. prediction and structural analyses indicate that both variants are most likely pathogenic.
神经元蜡样脂褐质沉积症（NCLs），也被称为巴顿病，是一组常染色体隐性溶酶体贮积症，其特征为神经退行性变、进行性认知衰退、运动障碍、共济失调、视力丧失、癫痫发作和过早死亡。迄今为止，超过13个基因的致病变异已与NCLs相关联。 编码一种内质网非糖基化跨膜蛋白，其参与溶酶体酸化。 中的突变导致晚婴儿型青少年NCL（JNCL）成人型NCL和库夫斯病。对两个患有JNCL的可用家族的成员进行了临床评估，并从同意参与的个体中采集了样本。通过全外显子组测序、桑格测序和家系分离分析进行分子研究。此外，对鉴定出的 变异进行了预测分析和结构建模。我们报告了来自两个希腊塞浦路斯家族（915和926家族）的三名患有JNCL患者的临床和遗传发现。所有患者均为男性，首发症状出现在6岁时。926家族的先证者表现出运动能力丧失、共济失调、痉挛、癫痫发作和癫痫。915家族的先证者有共济失调、痉挛、构音障碍、肌张力障碍和智力残疾。两名先证者均未表现出视力和/或听力丧失的初始迹象。926家族的分子分析揭示了两个 双等位基因变异：新的p.Tyr295Cys和已知的p.Arg136His变异。在915家族中，两名患者均为p.Arg136His变异的纯合子。对这两个 变异的预测分析将它们表征为可能具有损害性且致病。变异的结构建模预测它们可能导致蛋白质结构分化。总之，我们描述了两个患有JNCL的不相关塞浦路斯家族。两个家族的 基因均有变异；然而，它们表现出略有不同的症状，值得注意的是，没有一名患者有视力丧失。预测和结构分析表明这两个变异很可能是致病的。
