MYO1EMutations and Childhood Familial Focal Segmental Glomerulosclerosis

Abstract

Background Focal segmental glomerulosclerosis (FSGS) is a kidney disease that presents with nephrotic syndrome and is often resistant to glucocorticosteroids and progresses to end-stage kidney disease in 50–70% of patients. Genetic studies in familial FSGS indicate that it is a disease of the podocytes, major components of the glomerular filtration barrier. However the molecular cause of over half of primary FSGS is unknown, and effective treatments have been elusive. Methods We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive linkage area in a family with autosomal recessive FSGS and sequenced a newly discovered gene in 52 unrelated FSGS patients. Immunohistochemistry was performed in human kidney biopsies and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. Results Two mutations (A159P and Y695X) in MYO1E, encoding the non-muscle class I myosin, myosin 1E (Myo1E), which segregated with FSGS in two independent pedigrees were identified. Patients were homozygous for the mutations and were resistant to glucocorticosteroids. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney biopsies in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and the tail domains of Myo1E. Conclusions MYO1E mutations lead to childhood onset steroid-resistant FSGS. These data support a role of Myo1E in podocyte function and the consequent integrity of the glomerular permselectivity barrier.

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children

“…The observed gene detection rate is most likely an underestimate, because until recently, the high cost and processing times of conventional Sanger sequencing allowed for screening of only a few genes selected according to age at disease onset, histopathology findings, and in familial cases, mode of inheritance. Also, within the lifetime of the registry, several new genes have been identified (5)-some as part of the activities of the PodoNet consortium (16,17). Our findings indicate that SRNS may be explained by rare abnormalities in a large number of genes.…”

Recent advances of animal model of focal segmental glomerulosclerosis

“…Myosin 1e (Myo1e) is one of the two Src homology 3 domain-containing "long-tailed" type I myosins in Actin filament cross-linking protein/Interacts with integrins and strengthens the podocyte-GBM interaction Atypical protein kinase C [68][69][70][71] Tight junctions/Formation of Par complex and interacts with slit diaphragm Rhophilin-1 [80] Rho GTPase activating protein 24 [80] Cytoplasm/Rho GTPase-interacting protein, integrity of glomerular filtration barrier Angiotensin II receptor [55][56][57] Angiotensin-converting enzyme [55][56][57] Membrane/pseudocyst formation at podocyte CD2-associated protein [65][66][67] CD2-associated protein [64] Insertion site of the slit diaphragm/Formation SD complex with podocin and nephrin Laminin subunit beta-2 [81][82][83][84] Laminin subunit beta-2 [81][82][83][84] Podocyte anchoring and differentiation in GBM microRNA 193α [74,75] Cytoplasm/Inhibition of expression of WT-1 Myosin 1e [49,50] Myosin 1e [49,50] Actin binding long-tailed motor protein/Regulation of actin cytoskeleton Nuclear factor of activated T cells [76,77] Transient receptor potential 6 [53,54] Membrane/the activation of calcineurin-NFAT/Wnt signaling via the increased calcium influx Podocin [46] Podocin [58,59] Insertion site of the SD/SD assembly and maintaining the signaling of nephrin Shroom family member 3 …”

“…Myo1e in humans has an important role in podocyte function and the consequent integrity of glomerular permselectivity barrier. The mutation leads to childhood onset steroid-resistant FSGS [50] (Table 2; Fig. 1).…”

Podocyte Mitosis – A Catastrophe

“…Moreover, mutation in Arhgap24 [40], a RhoA-activated Rac1 GTPase-activating protein that controls actin polymerization, was associated with FSGS. Recently, mutations in myosin 1E ( MYO1E ) an actin-dependent molecular motor, are associated with childhood-onset, glucocorticoid-resistant FSGS [41]. Finally, GLEPP1 - null mice do not exhibit proteinuria, but podocytes display morphological changes, such as broadening of the foot process [13].…”