Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome
Jia Rao, Shazia Ashraf, Weizhen Tan, Amelie T. van der Ven, Heon Yung Gee, Daniela A. Braun, Krisztina Fehér, Sudeep P. George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K. Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A. Kari, Sherif El Desoky, Neveen A. Soliman, Arvind Bagga, Shrikant Mane, Mohamad A. Jairajpuri, Richard P. Lifton, Seema Khurana, Jose C. Martins, Friedhelm Hildebrandt
Jia Rao, Shazia Ashraf, Weizhen Tan, Amelie T. van der Ven, Heon Yung Gee, Daniela A. Braun, Krisztina Fehér, Sudeep P. George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K. Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A. Kari, Sherif El Desoky, Neveen A. Soliman, Arvind Bagga, Shrikant Mane, Mohamad A. Jairajpuri, Richard P. Lifton, Seema Khurana, Jose C. Martins, Friedhelm Hildebrandt
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Research Article Nephrology

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

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.

Authors

Jia Rao, Shazia Ashraf, Weizhen Tan, Amelie T. van der Ven, Heon Yung Gee, Daniela A. Braun, Krisztina Fehér, Sudeep P. George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K. Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A. Kari, Sherif El Desoky, Neveen A. Soliman, Arvind Bagga, Shrikant Mane, Mohamad A. Jairajpuri, Richard P. Lifton, Seema Khurana, Jose C. Martins, Friedhelm Hildebrandt

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Figure 1

Renal histology, pedigree analysis and homozygosity mapping in family A2438 diagnosed with SRNS.

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Renal histology, pedigree analysis and homozygosity mapping in family A2...
(A) Renal histology of individuals with AVIL mutation. Renal histology by light microscopy (LM) from individual A2438_22 with PAS staining showed DMS (scale bars: 50 μm). Transmission electron microscopy (TEM) image from individual A2438_22 showed diffuse foot process effacement (arrowheads). Original magnification, ×7,000. (B) Pedigree for index family A2438. Squares represent males, circles females, black symbols indicate affected persons, and white symbols designate unaffected persons. The double line indicates the consanguineous family. (C) Homozygosity mapping identified recessive candidate loci. In individual A2438_22 with SRNS, nonparametric lod (NPL) scores were calculated and plotted across the human genome. The x axis plots Affymetrix 250K StyI array SNP positions on human chromosomes concatenated from p-ter (left) to q-ter (right). Genetic distance is given in centimorgans (cM). Maximum NPL peaks (red circles) indicate 14 candidate regions of homozygosity by descent as recessive candidate loci. The AVIL locus (arrowhead) is positioned within one of the maximum NPL peaks on chromosome 12q.