Department of Pediatrics, Medical School, University of Messina, Messina, Italy.
Curr Opin Pediatr. 2012 Aug;24(4):512-7. doi: 10.1097/MOP.0b013e328354ccdf.
Wolfram syndrome 1 (WS1) is an autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DI DM OA D syndrome) associated with other variable clinical manifestations. The causative gene for WS1 (WFS1) encoding wolframin maps to chromosome 4p16.1. Wolframin has an important function in maintaining the homeostasis of the endoplasmic reticulum (ER) in pancreatic β cells. Recently, another causative gene, CISD2, has been identified in patients with a type of Wolfram syndrome (WS2) resulting in early optic atrophy, diabetes mellitus, deafness, decreased lifespan, but not diabetes insipidus. The CISD2-encoded protein ERIS (endoplasmic reticulum intermembrane small protein) also localizes to ER, but does not interact directly with wolframin. ERIS maps to chromosome 4q22.
Numerous studies have shown an interesting similarity between WFS1 and CISD2 genes. Experimental studies demonstrated that the Cisd2 knockout (Cisd2) mouse shows premature aging and typical symptoms of Wolfram syndrome. These researches provide interesting insight into the relation of neurodegenerative diseases, mitochondrial disorders, and autophagy and are useful for the pathophysiological understanding of both Wolfram syndrome and mitochondrial-mediated premature aging.
The knowledge of WS1 and WS2 pathogenesis, and of the interactions between WFS1 and CISD2 genes, is useful for accurate diagnostic classification and for diagnosis of presymptomatic individuals.
Wolfram 综合征 1 型（WS1）是一种常染色体隐性遗传疾病，其特征为尿崩症、糖尿病、视神经萎缩和耳聋（DI-DM-OA-D 综合征），伴有其他可变的临床表现。WS1 的致病基因（WFS1）编码沃弗林，定位于 4p16.1 染色体上。沃弗林在维持胰腺β细胞内质网（ER）的内稳态方面具有重要作用。最近，另一个致病基因 CISD2 已在导致早发性视神经萎缩、糖尿病、耳聋、寿命缩短但无尿崩症的 Wolfram 综合征 2 型（WS2）患者中被鉴定出来。CISD2 编码的 ERIS（内质网膜间小蛋白）也定位于 ER，但不与沃弗林直接相互作用。ERIS 定位于 4q22 染色体。
大量研究表明 WFS1 和 CISD2 基因之间存在有趣的相似性。实验研究表明 Cisd2 敲除（Cisd2）小鼠表现出过早衰老和典型的 Wolfram 综合征症状。这些研究为神经退行性疾病、线粒体疾病和自噬之间的关系提供了有趣的见解，有助于理解 Wolfram 综合征和线粒体介导的过早衰老的病理生理学。
对 WS1 和 WS2 发病机制以及 WFS1 和 CISD2 基因相互作用的了解，有助于进行准确的诊断分类和对症状前个体的诊断。
