Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA.
Mass Eye and Ear Infirmary, Harvard School of Medicine, Boston, MA, USA.
Mol Genet Genomic Med. 2021 Jan;9(1):e1566. doi: 10.1002/mgg3.1566. Epub 2020 Dec 11.
Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. The most frequent cause of juvenile nephronophthisis is a mutation in the nephronophthisis type 1 (NPHP1) gene. NPHP1 encodes the protein nephrocystin-1, which functions at the transition zone (TZ) of primary cilia.
We report a 9-year-old Senior-Loken syndrome boy with NPHP1 deletion, who presents with bilateral vision decrease and cystic renal disease. Renal function deteriorated to require bilateral nephrectomy and renal transplant. We performed immunohistochemistry, H&E staining, and electron microscopy on the renal sample to determine the subcellular distribution of ciliary proteins in the absence of NPHP1.
Immunohistochemistry and electron microscopy of the resected kidney showed disorganized cystic structures with loss of cilia in renal tubules. Phosphoinositides have been recently recognized as critical components of the ciliary membrane and immunostaining of kidney sections for phosphoinositide 5-phosphatase, INPP5E, showed loss of staining compared to healthy control. Ophthalmic examination showed decreased electroretinogram consistent with early retinal degeneration.
The decreased expression of INPP5E specifically in the primary cilium, coupled with disorganized cilia morphology, suggests a novel role of NPHP1 that it is involved in regulating ciliary phosphoinositide composition in the ciliary membrane of renal tubular cells.
Senior-Loken 综合征是一种罕见的遗传性疾病，表现为肾单位肾痨和视网膜变性，导致终末期肾病和进行性失明。青少年肾单位肾痨最常见的原因是 nephronophthisis 类型 1（NPHP1）基因突变。NPHP1 编码的蛋白 nephrocystin-1 在初级纤毛的过渡区（TZ）发挥作用。
我们报道了一例 9 岁的 Senior-Loken 综合征伴 NPHP1 缺失的男孩，表现为双侧视力下降和囊性肾病。肾功能恶化，需要双侧肾切除术和肾移植。我们对肾组织进行了免疫组织化学、H&E 染色和电子显微镜检查，以确定在没有 NPHP1 的情况下，纤毛蛋白的亚细胞分布。
切除肾脏的免疫组织化学和电子显微镜显示，肾小管中的纤毛失去了囊性结构紊乱。磷酸肌醇已被最近认为是纤毛膜的关键组成部分，对肾组织切片进行磷酸肌醇 5-磷酸酶（INPP5E）的免疫染色显示与健康对照组相比，染色丢失。眼科检查显示视网膜变性早期的视网膜电图降低。
INPP5E 在初级纤毛中的表达减少，加上纤毛形态紊乱，提示 NPHP1 参与调节肾单位纤毛膜中纤毛磷酸肌醇的组成具有新的作用。
