Department of Nephrology and Transplantation, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Laboratoire de Spectrométrie de Masse BioOrganique, CNRS, IPHC, UMR 7178, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
Mol Genet Genomic Med. 2021 May;9(5):e1658. doi: 10.1002/mgg3.1658. Epub 2021 Mar 29.
Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent.
We performed exome sequencing on a three-generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy.
The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end-stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein.
This is the first description of a peculiar association combining a PODXL stop-gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy.
足细胞蛋白（PODXL）是一种高度唾液酸化的黏附糖蛋白，在足细胞生理中发挥重要作用。最近，PODXL 基因中的错义和无义显性变异与局灶节段性肾小球硬化症（FSGS）相关，FSGS 是肾病综合征和肾衰竭的主要原因。然而，它们的组织学描述是肤浅的或不存在的。
我们对一个三代家族中受非典型肾小球肾病影响的患者进行了外显子组测序，并通过光镜和电镜对疾病进行了特征描述。
该疾病的特征是 FSGS 特征和肾小球基底膜重复。六名家族成员表现出慢性蛋白尿，从无肾衰竭的轻度表现到终末期肾病的严重形式不等。受影响的双胞胎姐妹、她们受影响的母亲、健康的父亲和健康的叔叔进行外显子组测序发现，PODXL 基因中的一个新的无义变异与疾病共分离（c.1453C>T，NM_001018111），该基因已知在肾脏中表达，当发生突变时会导致肾病。该变异预计会导致提前终止密码子（p.Q485*），从而导致蛋白的胞质内尾巴缺失。
这是第一个描述结合 PODXL 终止增益变异与 FSGS 和膜增殖性肾小球肾炎特征的奇特关联的描述，通过光镜和电镜进行了描述。
