ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Eur J Endocrinol. 2021 Mar;184(3):455-468. doi: 10.1530/EJE-20-0636.
DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome.
Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined.
The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA.
This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.
DNAJC3，也称为 P58IPK，是 Hsp40 家族成员，与 PKR 样内质网定位的 eIF2α 激酶（PERK）相互作用并抑制其活性。小鼠 Dnajc3 缺失导致胰岛β细胞丢失和糖尿病。DNAJC3 的功能丧失突变导致早发性糖尿病和多系统神经退行性变。本研究旨在探讨两例无亲缘关系的早发性综合征性糖尿病患者的遗传病因，并阐明该综合征中β细胞衰竭的机制。
进行全外显子组测序，并通过 Sanger 测序证实了变异。通过 RNAi 沉默 INS-1E 细胞、原代大鼠β细胞、人胰岛和诱导多能干细胞衍生的β细胞中的 DNAJC3。评估β细胞功能和细胞凋亡，并检查潜在的凋亡介质。
两名患者表现为青少年发病的糖尿病、身材矮小、甲状腺功能减退、神经退行性变、面部畸形、听力减退、小头症和骨骼畸形。他们携带 DNAJC3 的新型复合杂合和纯合失活突变。DNAJC3 沉默并不损害胰岛素含量或分泌。相反，敲低诱导大鼠和人β细胞凋亡，并进一步使细胞对内质网应激敏感，通过促凋亡 Bcl-2 蛋白 BIM 和 PUMA 触发线粒体凋亡。
本报告证实了先前描述的特征，并扩展了综合征性 DNAJC3 糖尿病的临床谱，这是内质网应激反应 PERK 途径的五种单基因糖尿病形式之一。DNAJC3 缺乏可能通过 BIM 和 PUMA 依赖性激活线粒体凋亡途径导致β细胞丢失。
