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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice.

ABSTRACT: Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42^Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1ap^Ex3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.

SUBMITTER: Majmundar AJ

PROVIDER: S-EPMC10763988 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice.

Majmundar Amar J AJ Buerger Florian F Forbes Thomas A TA Klämbt Verena V Schneider Ronen R Deutsch Konstantin K Kitzler Thomas M TM Howden Sara E SE Scurr Michelle M Tan Ker Sin KS Krzeminski Mickaël M Widmeier Eugen E Braun Daniela A DA Lai Ethan E Ullah Ihsan I Amar Ali A Kolb Amy A Eddy Kaitlyn K Chen Chin Heng CH Salmanullah Daanya D Dai Rufeng R Nakayama Makiko M Ottlewski Isabel I Kolvenbach Caroline M CM Onuchic-Whitford Ana C AC Mao Youying Y Mann Nina N Nabhan Marwa M MM Rosen Seymour S Forman-Kay Julie D JD Soliman Neveen A NA Heilos Andreas A Kain Renate R Aufricht Christoph C Mane Shrikant S Lifton Richard P RP Shril Shirlee S Little Melissa H MH Hildebrandt Friedhelm F

Science advances 20210101 1

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration ...[more]

PMID: 33523862

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Project description:Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human and mice. We identified two families carrying a deletion encompassing IFT74 exon 2, the first coding exon, resulting in a protein lacking the first 40 amino acids and two individuals carrying biallelic splice site mutations. Homozygous exon 2 deletion cases presented a ciliary chondrodysplasia with narrow thorax and progressive growth retardation along with a mucociliary clearance disorder phenotype with severely shorted cilia. Splice site variants resulted in a lethal skeletal chondrodysplasia phenotype. In mice, removal of the first 40 amino acids likewise results in a motile cilia phenotype but with little effect on primary cilia structure. Mice carrying this allele are born alive but are growth restricted and developed hydrocephaly in the first month of life. In contrast, a strong, likely null, allele of Ift74 in mouse completely blocks ciliary assembly and causes severe heart defects and midgestational lethality. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia resulting from increased mechanical stress and repair needs could account for the motile cilia phenotype observed in human and mice.

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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice.

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Recessive <i>NOS1AP</i> variants impair actin remodeling and cause glomerulopathy in humans and mice.

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Recessive NOS1AP variants impair actin remodeling and cause glomerulopathy in humans and mice.

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Recessive &lt;i&gt;NOS1AP&lt;/i&gt; variants impair actin remodeling and cause glomerulopathy in humans and mice.

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Recessive <i>NOS1AP</i> variants impair actin remodeling and cause glomerulopathy in humans and mice.