@article {502, title = { and Mutations Implicate RAB5 Regulation in Nephrotic Syndrome.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Aug}, pages = {2123-2138}, abstract = {

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS.

METHODS: To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like nephrocytes.

RESULTS: We identified conserved, homozygous missense mutations of in two families with early-onset NS and a homozygous missense mutation of in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of or bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived mutations reduced nephrin-GAPVD1 binding affinity. In , silencing impaired endocytosis and caused mistrafficking of the nephrin ortholog.

CONCLUSIONS: Mutations in and probably in are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121312}, author = {Hermle, Tobias and Schneider, Ronen and Schapiro, David and Braun, Daniela A and van der Ven, Amelie T and Warejko, Jillian K and Daga, Ankana and Widmeier, Eugen and Nakayama, Makiko and Jobst-Schwan, Tilman and Majmundar, Amar J and Ashraf, Shazia and Rao, Jia and Finn, Laura S and Tasic, Velibor and Hernandez, Joel D and Bagga, Arvind and Jalalah, Sawsan M and El Desoky, Sherif and Kari, Jameela A and Laricchia, Kristen M and Lek, Monkol and Rehm, Heidi L and MacArthur, Daniel G and Mane, Shrikant and Lifton, Richard P and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {457, title = {Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 12 01}, pages = {4257-4269}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.

}, keywords = {Actin-Related Protein 2-3 Complex, Cell Movement, Diglycerides, Female, Humans, Male, Microfilament Proteins, Mutation, Nephrotic Syndrome, Phosphoinositide Phospholipase C, Podocytes, Pseudopodia}, issn = {1558-8238}, doi = {10.1172/JCI94138}, author = {Rao, Jia and Ashraf, Shazia and Tan, Weizhen and van der Ven, Amelie T and Gee, Heon Yung and Braun, Daniela A and Feh{\'e}r, Krisztina and George, Sudeep P and Esmaeilniakooshkghazi, Amin and Choi, Won-Il and Jobst-Schwan, Tilman and Schneider, Ronen and Schmidt, Johanna Magdalena and Widmeier, Eugen and Warejko, Jillian K and Hermle, Tobias and Schapiro, David and Lovric, Svjetlana and Shril, Shirlee and Daga, Ankana and Nayir, Ahmet and Shenoy, Mohan and Tse, Yincent and Bald, Martin and Helmchen, Udo and Mir, Sevgi and Berdeli, Afig and Kari, Jameela A and El Desoky, Sherif and Soliman, Neveen A and Bagga, Arvind and Mane, Shrikant and Jairajpuri, Mohamad A and Lifton, Richard P and Khurana, Seema and Martins, Jose C and Hildebrandt, Friedhelm} }