PDF(Pubmed)
Abstract：
CCDC186 protein is involved in the maturation of dense-core vesicles (DCVs) in the trans-Golgi network in neurons and endocrine cells. Mutations in genes involved in DCV regulation, other than CCDC186, have been described in patients with neurodevelopmental disorders. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in CCDC186, had previously been described. However, no functional studies in any of these two cases had been performed. We identified three patients from two gypsy families, unrelated to each other, with mutations in the CCDC186 gene. Clinically, all patients presented with seizures, frontotemporal atrophy, hypomyelination, recurrent infections, and endocrine disturbances such as severe non-ketotic hypoglycemia. Low levels of cortisol, insulin, or growth hormone could only be verified in one patient. All of them had a neonatal onset and died between 7 months and 4 years of age. Whole exome sequencing identified a homozygous variant in the CCDC186 gene (c.2215C>T, p.Arg739Ter) in the index patients of both families. Protein expression studies demonstrated that CCDC186 was almost undetectable in fibroblasts and muscle tissue. These observations correlated with the transcriptomic analysis performed in fibroblasts in one of the patients, which showed a significant reduction of CCDC186 mRNA levels. Our study provides functional evidence that mutations in this gene have a pathogenic effect on the protein and reinforces CCDC186 as a new disease-associated gene. In addition, mutations in CCDC186 could explain the combined endocrine and neurologic alterations detected in our patients.
摘要：
CCDC186蛋白参与神经元和内分泌细胞跨高尔基体网络中致密核心囊泡（DCV）的成熟。涉及DCV调控的基因突变，除CCDC186外，已在神经发育障碍患者中被描述。迄今为止,只有一个病人,在1000个病例的大型测序研究中，以前曾描述过一例CCDC186变异病例。然而,在这2例病例中均未进行功能研究.我们确定了来自两个吉普赛家庭的三个病人,彼此无关，CCDC186基因突变。临床上,所有出现癫痫发作的病人,额颞叶萎缩,髓鞘减少,反复感染,和内分泌紊乱，如严重的非酮症性低血糖。低水平的皮质醇,胰岛素，或生长激素只能在一名患者中得到证实。他们都是新生儿发病，在7个月至4岁之间死亡。全外显子组测序确定了CCDC186基因中的纯合变体（c.2215C>T，p.Arg739Ter）在两个家庭的索引患者中。蛋白质表达研究表明，CCDC186在成纤维细胞和肌肉组织中几乎检测不到。这些观察结果与其中一名患者的成纤维细胞中进行的转录组学分析相关，显示CCDC186mRNA水平显着降低。我们的研究提供了功能性证据，表明该基因的突变对蛋白质具有致病作用，并加强了CCDC186作为新的疾病相关基因。此外,CCDC186中的突变可以解释我们患者中检测到的内分泌和神经系统联合改变.
