Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Pediatr Nephrol. 2023 Feb;38(2):439-449. doi: 10.1007/s00467-022-05634-x. Epub 2022 Jun 20.
Pathogenic mutations in the non-muscle single-headed myosin, myosin 1E (Myo1e), are a rare cause of pediatric focal segmental glomerulosclerosis (FSGS). These mutations are biallelic, to date only reported as homozygous variants in consanguineous families. Myo1e regulates the actin cytoskeleton dynamics and cell adhesion, which are especially important for podocyte functions.
DNA and RNA sequencing were used to identify novel MYO1E variants associated with FSGS. We studied the effects of these variants on the localization of Myo1e in kidney sections. We then analyzed the clinical and histological observations of all known pathogenic MYO1E variants.
We identified a patient compound heterozygote for two novel variants in MYO1E and a patient homozygous for a deletion of exon 19. Computer modeling predicted these variants to be disruptive. In both patients, Myo1e was mislocalized. As a rule, pathogenic MYO1E variants map to the Myo1e motor and neck domain and are most often associated with steroid-resistant nephrotic syndrome in children 1-11 years of age, leading to kidney failure in 4-10 years in a subset of patients. The ultrastructural features are the podocyte damage and striking diffuse and global Alport-like glomerular basement membrane (GBM) abnormalities.
We hypothesize that MYO1E mutations lead to disruption of the function of podocyte contractile actin cables resulting in abnormalities of the podocytes and the GBM and dysfunction of the glomerular filtration barrier. The characteristic clinicopathological data can help to tentatively differentiate this condition from other genetic podocytopathies and Alport syndrome until genetic testing is done. A higher resolution version of the Graphical abstract is available as Supplementary information.
非肌肉单头肌球蛋白 1E（Myo1e）中的致病性突变是小儿局灶节段性肾小球硬化症（FSGS）的罕见病因。这些突变是双等位基因的，迄今为止仅在近亲家庭中报告为纯合变异体。Myo1e 调节肌动蛋白细胞骨架动力学和细胞黏附，这对足细胞功能尤为重要。
使用 DNA 和 RNA 测序来鉴定与 FSGS 相关的新型 MYO1E 变体。我们研究了这些变体对肾脏切片中 Myo1e 定位的影响。然后，我们分析了所有已知致病性 MYO1E 变体的临床和组织学观察结果。
我们鉴定了一名患者为 MYO1E 中的两个新型变体的复合杂合子，另一名患者为外显子 19 缺失的纯合子。计算机建模预测这些变体具有破坏性。在这两名患者中，Myo1e 均定位异常。通常，致病性 MYO1E 变体位于 Myo1e 运动和颈部结构域，最常与儿童 1-11 岁的类固醇难治性肾病综合征相关，导致部分患者在 4-10 岁时出现肾功能衰竭。超微结构特征是足细胞损伤和明显弥漫性和全球性阿尔波特样肾小球基底膜（GBM）异常。
我们假设 MYO1E 突变导致足细胞收缩性肌动蛋白电缆的功能障碍，导致足细胞和 GBM 的异常以及肾小球滤过屏障的功能障碍。特征性的临床病理数据有助于在进行基因检测之前，暂时将这种情况与其他遗传足细胞病和阿尔波特综合征区分开来。图形摘要的更高分辨率版本可作为补充信息提供。
