Grieco Giuseppina, Montefusco Sandro, Nusco Edoardo, Capuozzo Antonella, Cervellini Francesca, Polishchuk Elena, Bishop Martha, Miele Antonio, D'Apolito Luciano, La Vecchia Claudia, Aurilia Miriam, Schiavo Michela, Staiano Leopoldo, Cesana Marcella, Oberman Rebecca, Lynch Anna V, Musolino Patricia, Trepiccione Francesco, Grishchuk Yulia, Medina Diego Luis
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Department of Neurology, Massachusetts General Hospital Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts.
J Am Soc Nephrol. 2025 Apr 1;36(4):587-601. doi: 10.1681/ASN.0000000567. Epub 2024 Dec 4.
Loss-of-function mutations in the lysosomal channel transient receptor potential cation channel (TRPML-1) cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood.
A cross-sectional review of medical records from 21 patients with MLIV (ages 3–43 years) was conducted to assess kidney function impairment. In addition, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo kidney filtration measurements.
Of the 21 patients with MLIV, only adults were diagnosed with stage 2–3 CKD. Laboratory abnormalities included lower eGFR and higher levels BUN/creatine in blood and proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor–mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. In addition, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the proinflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, adeno-associated viral–mediated TRPML-1 gene delivery reversed key pathological phenotypes in MLIV mice, underscoring TRPML-1's critical role in kidney function.
Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV.
溶酶体通道瞬时受体电位阳离子通道（TRPML-1）的功能丧失突变会导致IV型粘脂贮积症（MLIV），这是一种罕见的溶酶体贮积病，其特征为神经缺陷、进行性视力丧失和胃酸缺乏。最近的报告强调了MLIV患者在二三十岁时会出现肾脏疾病和肾衰竭；然而，导致肾功能障碍的分子机制仍知之甚少。
对21例MLIV患者（年龄3至43岁）的病历进行横断面回顾，以评估肾功能损害情况。此外，我们研究了不同年龄的MLIV小鼠的肾脏表型，以及TRPML-1基因沉默的人肾细胞和野生型及MLIV小鼠的原代肾小管细胞。采用免疫组织学和细胞生物学方法对肾单位结构、内溶酶体区室和炎症进行表型分析。通过对小鼠尿液的蛋白质组分析和体内肾脏滤过测量来评估肾功能。
在21例MLIV患者中，只有成年患者被诊断为2至3期慢性肾脏病。实验室异常包括估算肾小球滤过率较低、血液中尿素氮/肌酐水平较高以及蛋白尿。在MLIV小鼠中，我们观察到近端和远端肾小管内溶酶体形态、功能发生显著改变，自噬受损。这导致巨膜蛋白（LRP2）在近端肾小管细胞的顶下区域积聚，表明顶端受体介导的内吞作用受阻。体内和体外实验证实，MLIV近端肾小管细胞的液相内吞作用降低，包括β-乳球蛋白、转铁蛋白和白蛋白在内的配体摄取受损。尿液分析显示MLIV小鼠存在肾小管蛋白尿和酶尿。此外，疾病早期的特征是炎症标志物增加、纤维化以及促炎转录因子NF-κB激活，这与内溶酶体缺陷同时出现。重要的是，腺相关病毒介导的TRPML-1基因传递逆转了MLIV小鼠的关键病理表型；这突出了TRPML-1在肾功能中的关键作用。
我们的研究结果将TRPML-1功能障碍与MLIV患者肾脏疾病的发生联系起来。
