KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Gee, Heon Yung; Zhang, Fujian; Ashraf, Shazia; Kohl, Stefan; Sadowski, Carolin E.; Vega-Warner, Virginia; Zhou, Weibin; Lovric, Svjetlana; Fang, Humphrey; Nettleton, Margaret; Zhu, Jun-yi; Hoefele, Julia; Weber, Lutz T.; Podracká, Ľudmila; Böör, A; Fehrenbach, Henry; Innis, Jeffrey W.; Washburn, Joseph; Levy, Shawn; Lifton, Richard P.; Otto, Edgar A.; Han, Zhe; Hildebrandt, Friedhelm

doi:10.1172/jci79504

Cited by 163 publications

(159 citation statements)

References 35 publications

(38 reference statements)

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“…Inability to degrade toxic long-chain bases led to decreased viability and slowed growth. Human WT and p.Glu132Gly mutant SGPL1 were found to be able to partially restore dpl1Δ, while p.Arg222Gln, p.Ser346Ile, and p.Tyr416Cys as well as frameshift mutants p.Arg278Glyfs*17 and p.Ser3Lysfs*11 showed no improved growth compared with dpl1Δ ( Figure 2N and Supplemental Figure 7A), consistent with S1P has previously been implicated in the regulation of RHOlike small GTPases (RHOA/RAC1/CDC42), and disruption of RAC1 signaling was previously implicated in the pathogenesis of SRNS (13)(14)(15). We therefore tested whether knockdown of SGPL1 would affect activation of the RHO-like small GTPases.…”

Section: Sgpl1 -/-Mice Exhibit Podocyte Foot Process Effacement Sgpl1supporting

confidence: 84%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

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169

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Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of diseaseassociated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

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Section: Sgpl1 -/-Mice Exhibit Podocyte Foot Process Effacement Sgpl1supporting

confidence: 84%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

Self Cite

169

174

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“…We expect that our system will allow for large numbers of candidate genes constituting the network of FSGS genes to be validated and that it will provide critical insight into the pathogenesis of this disease syndrome. In addition, our experimental approach (33). Rare variant analysis identified 6 new potential FSGS susceptibility genes.…”

Section: Sequencing Of Dna From Fsgs Patientsmentioning

confidence: 99%

A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

Yu¹,

Artomov²,

Brähler³

et al. 2016

Journal of Clinical Investigation

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“…We next examined the effect of AVIL on the PMR, which represents a relevant intermediate cellular phenotype in many forms of monogenic SRNS (8,10,12). We used the IncuCyte ZOOM video microscopy system, which monitors cell migration in real time.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, actin remodeling has also been implicated in NS (9). Defects in actin remodeling may be part of the reason why a defect in the podocyte migration rate (PMR) in cell culture has been established as a reliable intermediate phenotype in monogenic forms of SRNS (8,(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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

Rao¹,

Ashraf²,

Tan³

et al. 2017

Journal of Clinical Investigation

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KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Cited by 163 publications

References 35 publications

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

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

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