Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis.

Background: Primary ciliopathies are a heterogeneous group of rare disorders predominantly caused by autosomal-recessive genetic variants that disrupt non-motile ciliary function. They often manifest as a syndromic phenotype, frequently involving the kidney. Biallelic pathogenic variants in C2CD3 disrupt ciliogenesis and Sonic Hedgehog (SHH) signaling, resulting in a severe ciliopathy (Orofaciodigital syndrome XIV, OMIM 615948).

The CPLANE protein Fuzzy regulates ciliogenesis by suppressing actin polymerization at the base of the primary cilium via p190A RhoGAP.

The primary cilium decorates most eukaryotic cells and regulates tissue morphogenesis and maintenance. Structural or functional defects of primary cilium result in ciliopathies, congenital human disorders affecting multiple organs. Pathogenic variants in the ciliogenesis and planar cell polarity effectors (CPLANE) genes FUZZY, INTU and WDPCP disturb ciliogenesis, causing severe ciliopathies in humans and mice.

Wilms' tumor gene 1: lessons from the interface between kidney development and cancer.

In 1990, mutations of the Wilms' tumor-1 gene (), encoding a transcription factor in the embryonic kidney, were found in 10-15% of Wilms' tumors; germline mutations were associated with hereditary syndromes involving glomerular and reproductive tract dysplasia. For more than three decades, these discoveries prompted investigators to explore the embryonic role of WT1 and the mechanisms by which loss of leads to malignant transformation. Here, we discuss how alternative splicing of generates isoforms that act in a context-specific manner to activate or repress target gene transcription.

Advancing Discovery Research in Nephrology in Canada: A Conference Report From the 2021 Molecules and Mechanisms Mediating Kidney Health and Disease (M3K) Scientific Meeting and Investigator Summit.

Purpose Of Conference: New discoveries arising from investigations into fundamental aspects of kidney development and function in health and disease are critical to advancing kidney care. Scientific meetings focused specifically on fundamental biology of the kidney can facilitate interactions, support the development of collaborative groups, and accelerate translation of key findings. The Canadian fundamental kidney researcher community has lacked such a forum.

Can Peer Review Be Kinder? Supportive Peer Review: A Re-Commitment to Kindness and a Call to Action.

Peer review aims to select articles for publication and to improve articles before publication. We believe that this process can be infused by kindness without losing rigor. In 2014, the founding editorial team of the (CJKHD) made an explicit commitment to treat authors as we would wish to be treated ourselves.

Loss of Planar Cell Polarity Effector Fuzzy Causes Renal Hypoplasia by Disrupting Several Signaling Pathways.

In vertebrates, the planar cell polarity (PCP) pathway regulates tissue morphogenesis during organogenesis, including the kidney. Mutations in human PCP effector proteins have been associated with severe syndromic ciliopathies. Importantly, renal hypoplasia has been reported in some patients.

Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis.

Craniosynostosis is a birth defect occurring in approximately one in 2000 live births, where premature fusion of the cranial bones inhibits growth of the skull during critical periods of brain development. The resulting changes in skull shape can lead to compression of the brain, causing severe complications. While we have some understanding of the molecular pathology of craniosynostosis, a large proportion of cases are of unknown genetic aetiology.

Planar cell polarity pathway in kidney development, function and disease.

Planar cell polarity (PCP) refers to the coordinated orientation of cells in the tissue plane. Originally discovered and studied in Drosophila melanogaster, PCP is now widely recognized in vertebrates, where it is implicated in organogenesis. Specific sets of PCP genes have been identified.

Differential role of planar cell polarity gene Vangl2 in embryonic and adult mammalian kidneys.

Planar cell polarity (PCP) pathway is crucial for tissue morphogenesis. Mutations in PCP genes cause multi-organ anomalies including dysplastic kidneys. Defective PCP signaling was postulated to contribute to cystogenesis in polycystic kidney disease.

From podocyte biology to novel cures for glomerular disease.

The podocyte is a key component of the glomerular filtration barrier. Podocyte dysfunction is central to the underlying pathophysiology of many common glomerular diseases, including diabetic nephropathy, glomerulonephritis and genetic forms of nephrotic syndrome. Collectively, these conditions affect millions of people worldwide, and account for the majority of kidney diseases requiring dialysis and transplantation.

Use of genomic and functional analysis to characterize patients with steroid-resistant nephrotic syndrome.

Background: Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups.

Ste20-like kinase, SLK, a novel mediator of podocyte integrity.

SLK is essential for embryonic development and may play a key role in wound healing, tumor growth, and metastasis. Expression and activation of SLK are increased in kidney development and during recovery from ischemic acute kidney injury. Overexpression of SLK in glomerular epithelial cells/podocytes in vivo induces injury and proteinuria.

New insights into precursors of renal endothelium.

The kidney vasculature is extremely complex, yet, despite recent progress, our understanding of how the renal vascular system develops is limited. By using advanced tissue engineering techniques and in vivo and in vitro depletion of specific populations of endothelial cell precursors, Halt et al. have identified a CD146-expressing precursor as an important player in the development of the renal vasculature.

Novel unbiased assay for circulating podocyte-toxic factors associated with recurrent focal segmental glomerulosclerosis.

Focal segmental glomerular sclerosis (FSGS) is an irreversible renal pathology characterized by podocyte detachment from the glomerular basement membrane, hyalinosis, and sclerosis. Clinically, it manifests with proteinuria and progressive loss of glomerular filtration. Primary idiopathic FSGS can occur in isolation and frequently progresses to end-stage renal disease, requiring dialysis or kidney transplantation.

Wilms Tumor Suppressor, WT1, Cooperates with MicroRNA-26a and MicroRNA-101 to Suppress Translation of the Polycomb Protein, EZH2, in Mesenchymal Stem Cells.

Hereditary forms of Wilms arise from developmentally arrested clones of renal progenitor cells with biallelic mutations of WT1; recently, it has been found that Wilms tumors may also be associated with biallelic mutations in DICER1 or DROSHA, crucial for miRNA biogenesis. We have previously shown that a critical role for WT1 during normal nephrogenesis is to suppress transcription of the Polycomb group protein, EZH2, thereby de-repressing genes in the differentiation cascade. Here we show that WT1 also suppresses translation of EZH2.

The planar cell polarity protein Vangl2 is required for retinal axon guidance.

Vangl2 plays a critical role in the establishment of planar cell polarity (PCP). Previously, we detected expression of Vangl2 in the developing retina during late embryogenesis, which led us to investigate the possible role of Vangl2-mediated PCP signaling in eye development. We have generated a Vangl2(BGeo) knock-in mouse allowing us to evaluate Vangl2 mRNA expression during retinal development, and used an isoform-specific antibody to examine Vangl2 protein expression in cryosections.

Deficiency of the planar cell polarity protein Vangl2 in podocytes affects glomerular morphogenesis and increases susceptibility to injury.

The planar cell polarity (PCP) signaling pathway is crucial for tissue morphogenesis. Van Gogh-like protein 2 (Vangl2) is central in the PCP pathway; in mice, Vangl2 loss is embryonically lethal because of neural tube defects, and mutations in Vangl2 are associated with human neural tube defects. In the kidney, PCP signaling may be important for tubular morphogenesis and organization of glomerular epithelial cells (podocytes) along the glomerular basement membrane.

Planar cell polarity pathway regulates nephrin endocytosis in developing podocytes.

The noncanonical Wnt/planar cell polarity (PCP) pathway controls a variety of cell behaviors such as polarized protrusive cell activity, directional cell movement, and oriented cell division and is crucial for the normal development of many tissues. Mutations in the PCP genes cause malformation in multiple organs. Recently, the PCP pathway was shown to control endocytosis of PCP and non-PCP proteins necessary for cell shape remodeling and formation of specific junctional protein complexes.

The PCP effector Fuzzy controls cilial assembly and signaling by recruiting Rab8 and Dishevelled to the primary cilium.

The planar cell polarity (PCP) pathway controls multiple cellular processes during vertebrate development. Recently the PCP pathway was implicated in ciliogenesis and in ciliary function. The primary cilium is an apically projecting solitary organelle that is generated via polarized intracellular trafficking.

An expanding role of Vangl proteins in embryonic development.

The mammalian Vangl1 and Vangl2 genes were discovered a decade ago through their association with neural tube defects, in particular the presence of Vangl2 mutations in independent alleles of the mouse mutant Loop-tail (Lp), a mouse model of the severe neural tube defect craniorachischisis. Vangl1 and Vangl2 variants have also been detected in familial and sporadic cases of spina bifida. Vangl proteins are highly conserved in evolution with relatives in flies, and distant invertebrates and vertebrates.