PDF(Pubmed)
Abstract：
The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.
摘要：
BiP共伴侣DNAJC3在ER应激期间保护细胞。在老鼠身上,DNAJC3的缺乏导致β细胞凋亡和高血糖的逐渐发作。在人类中,双等位基因DNAJC3变异导致多系统疾病，包括早发性糖尿病。最近,高胰岛素血症性低血糖（HH）已被认为是该综合征的一部分。本报告提供了一个由DNAJC3变体引起的HH个体的案例研究，并概述了HH和DNAJC3变体个体的代谢表型。研究表明，HH可能是DNAJC3缺乏症的主要症状，并且可以持续到青春期。此外,在年轻的DNACJ3敲除（K.O.）小鼠中分析了血糖和胰岛素释放，相当于人类婴儿。在实验上最年轻的4周龄小鼠中，体内血糖表型已经由总胰岛素分泌能力降低主导.然而,在细胞水平上，DNAJC3K.O.胰岛的胰岛素释放程度在合成活性增加（高糖刺激）期间较高。我们建议钙从内质网泄漏到细胞质中，由于Sec61通道的DNAJC3控制的门控中断，是HH最有可能的机制。这是仅通过破坏细胞内钙稳态来解释HH的第一个遗传机制。临床医生应筛查DNAJC3缺乏症中的HH，并在先天性高胰岛素血症的鉴别诊断中考虑DNAJC3变异。
