Pell John, Menon Madhav C
J Clin Invest. 2025 May 15;135(10). doi: 10.1172/JCI192687.
IgA nephropathy (IgAN) is a highly prevalent type of primary glomerulonephritis. IgAN involves mesangial deposition of immune complexes leading to complement activation, inflammation, and glomerular injury. A key hit for pathogenesis involves aberrant O-glycosylation in the hinge region of IgA. Despite its prevalence, however, the mechanisms underlying IgAN remain incompletely understood. In this issue of the JCI, Prakash and colleagues used whole-exome sequencing of two IgAN probands to identify loss-of-function variants in GALNT14 leading to loss of the enzyme GalNAc-T14, which is involved in O-glycosylation. The authors then performed a classical bedside-to-bench investigation using a Galnt14-/- mouse model and connected loss of GalNAc-T14 to excess IgA production, impaired B lymphocyte homing, and defective intestinal mucus production. These findings build a more unified understanding of IgAN pathogenesis from defective O-glycosylation with loss-of-function variants in GALNT14.
IgA肾病（IgAN）是一种高度常见的原发性肾小球肾炎。IgAN涉及免疫复合物在系膜沉积，导致补体激活、炎症和肾小球损伤。发病机制的一个关键因素是IgA铰链区异常O-糖基化。然而，尽管其常见，但IgAN的潜在机制仍未完全了解。在本期《临床研究杂志》中，普拉卡什及其同事对两名IgAN先证者进行了全外显子组测序，以鉴定导致参与O-糖基化的N-乙酰半乳糖胺基转移酶14（GalNAc-T14）缺失的功能丧失变异。然后，作者使用Galnt14基因敲除小鼠模型进行了经典的床边到实验室研究，将GalNAc-T14缺失与IgA产生过多、B淋巴细胞归巢受损和肠道黏液产生缺陷联系起来。这些发现从GALNT14功能丧失变异导致的缺陷O-糖基化方面，对IgAN发病机制建立了更统一的认识。
