PDF(Pubmed)
Abstract：
UNASSIGNED: Hereditary neurodevelopmental disorders (NDDs) are prevalent in poorly prognostic pediatric diseases, but the pathogenesis of NDDs is still unclear. Irregular myelination could be one of the possible causes of NDDs.
UNASSIGNED: Here, whole exome sequencing was carried out for a consanguineous Pakistani family with NDDs to identify disease-associated variants. The co-segregation of candidate variants in the family was validated using Sanger sequencing. The potential impact of the gene on NDDs has been supported by conservation analysis, protein prediction, and expression analysis. A novel homozygous variant DOP1A(NM_001385863.1):c.2561A>G was identified. It was concluded that the missense variant might affect the protein-protein binding sites of the critical MEC interaction region of DOP1A, and DOP1A-MON2 may cause stability deficits in Golgi-endosome protein traffic. Proteolipid protein (PLP) and myelin-associate glycoprotein (MAG) could be targets of the DOP1A-MON2 Golgi-endosome traffic complex, especially during the fetal stage and the early developmental stages. This further supports the perspective that disorganized myelinogenesis due to congenital DOP1A deficiency might cause neurodevelopmental disorders (NDDs).
UNASSIGNED: Our case study revealed the potential pathway of myelinogenesis-relevant NDDs and identified DOP1A as a potential NDDs-relevant gene in humans.
UNASSIGNED: Here, whole exome sequencing was carried out for a consanguineous Pakistani family with NDDs to identify disease-associated variants. The co-segregation of candidate variants in the family was validated using Sanger sequencing. The potential impact of the gene on NDDs has been supported by conservation analysis, protein prediction, and expression analysis. A novel homozygous variant DOP1A(NM_001385863.1):c.2561A>G was identified. It was concluded that the missense variant might affect the protein-protein binding sites of the critical MEC interaction region of DOP1A, and DOP1A-MON2 may cause stability deficits in Golgi-endosome protein traffic. Proteolipid protein (PLP) and myelin-associate glycoprotein (MAG) could be targets of the DOP1A-MON2 Golgi-endosome traffic complex, especially during the fetal stage and the early developmental stages. This further supports the perspective that disorganized myelinogenesis due to congenital DOP1A deficiency might cause neurodevelopmental disorders (NDDs).
UNASSIGNED: Our case study revealed the potential pathway of myelinogenesis-relevant NDDs and identified DOP1A as a potential NDDs-relevant gene in humans.
摘要：
■遗传性神经发育障碍（NDD）在预后不良的儿科疾病中普遍存在，但NDDs的发病机制尚不清楚。不规则的髓鞘形成可能是NDD的可能原因之一。
■这里，对一个有NDDs的巴基斯坦近亲家族进行全外显子组测序,以鉴定疾病相关变异.使用Sanger测序验证家族中候选变体的共分离。该基因对NDD的潜在影响已得到保守分析的支持，蛋白质预测，和表达分析。鉴定了新的纯合变体DOP1A(NM_001385863.1):c.2561A>G。结论是，错义变异可能会影响DOP1A的关键MEC相互作用区域的蛋白质-蛋白质结合位点，和DOP1A-MON2可能导致高尔基体-内体蛋白运输的稳定性缺陷。蛋白脂质蛋白（PLP）和髓鞘相关糖蛋白（MAG）可能是DOP1A-MON2高尔基体内体交通复合体的靶标，特别是在胎儿期和早期发育阶段。这进一步支持以下观点：由于先天性DOP1A缺乏而导致的髓鞘形成紊乱可能导致神经发育障碍（NDD）。
■我们的案例研究揭示了髓鞘生成相关NDD的潜在途径，并确定DOP1A是人类潜在的NDD相关基因。
■这里，对一个有NDDs的巴基斯坦近亲家族进行全外显子组测序,以鉴定疾病相关变异.使用Sanger测序验证家族中候选变体的共分离。该基因对NDD的潜在影响已得到保守分析的支持，蛋白质预测，和表达分析。鉴定了新的纯合变体DOP1A(NM_001385863.1):c.2561A>G。结论是，错义变异可能会影响DOP1A的关键MEC相互作用区域的蛋白质-蛋白质结合位点，和DOP1A-MON2可能导致高尔基体-内体蛋白运输的稳定性缺陷。蛋白脂质蛋白（PLP）和髓鞘相关糖蛋白（MAG）可能是DOP1A-MON2高尔基体内体交通复合体的靶标，特别是在胎儿期和早期发育阶段。这进一步支持以下观点：由于先天性DOP1A缺乏而导致的髓鞘形成紊乱可能导致神经发育障碍（NDD）。
■我们的案例研究揭示了髓鞘生成相关NDD的潜在途径，并确定DOP1A是人类潜在的NDD相关基因。
