Genomes of animals as different as sponges and humans show conservation of global architecture. Here we show that multiple genomic features including transposon diversity, developmental gene repertoire, physical gene order, and intron-exon organization are shattered in the tunicate Oikopleura, belonging to the sister group of vertebrates and retaining chordate morphology. Ancestral architecture of animal genomes can be deeply modified and may therefore be largely nonadaptive. This rapidly evolving animal lineage thus offers unique perspectives on the level of genome plasticity. It also illuminates issues as fundamental as the mechanisms of intron gain.

INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).

Abbreviations: NPHS2: nephrosis 2, steroid-resistant ; SRNS: steroid-resistant nephrotic syndrome Introductory paragraphNephrotic syndrome is the consequence of damage to the glomerular filtration barrier, and it refers to the clinical symptoms of heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. The steroidresistant form of nephrotic syndrome (SRNS) has a poor prognosis, as it often leads to endstage renal disease (ESRD) 1,2 . Mutations in more than 20 genes have been identified in monogenic forms of SRNS, most of which encode podocyte proteins3-5. NPHS2, encoding podocin, is the most frequently mutated of these genes and is responsible for 12-18% of SRNS cases 3,6,7 . Podocin accumulates in dimeric or oligomeric forms in lipid raft microdomains at the podocyte slit diaphragm, which is the key component of the glomerular filtration barrier. On the basis of its predicted structure, podocin belongs to the stomatin protein family, with a hairpin-like intramembrane loop and intracellular N and C termini. The C-terminal portions of both stomatin and podocin are responsible for dimerization 6,[8][9][10][11][12] .Individuals with NPHS2 mutations typically develop SRNS before 6 years of age and progress to ESRD during their first decade of life6. The phenotype can be less severe in the setting of a trans association of an NPHS2 mutation and the polymorphism c.686G>A (p.Arg229Gln, rs61747728), a genotype we hereafter denote as p.[Arg229Gln];[mut] that causes SRNS with a median age at diagnosis of 13 years (range, 0-39 years) and progression to ESRD by 26 years (range, 10-50 years) 7,[13][14][15][16][17][18] . Nevertheless, the p.Arg229Gln variant in the homozygous state does not cause SRNS 19,20 .On the basis of the 15× higher allele frequency of p.Arg229Gln (357/13,006, 2.7%) than the cumulative allele frequency of the known disease-causing variants 13-18,21-43 (24/13,006, 0.18%)

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Several genes, mainly involved in podocyte cytoskeleton regulation, have been implicated in familial forms of primary FSGS. We identified a homozygous missense mutation (p.P209L) in the TTC21B gene in seven families with FSGS. Mutations in this ciliary gene were previously reported to cause nephronophthisis, a chronic tubulointerstitial nephropathy. Notably, tubular basement membrane thickening reminiscent of that observed in nephronophthisis was present in patients with FSGS and the p.P209L mutation. We demonstrated that the TTC21B gene product IFT139, an intraflagellar transport-A component, mainly localizes at the base of the primary cilium in developing podocytes from human fetal tissue and in undifferentiated cultured podocytes. In contrast, in nonciliated adult podocytes and differentiated cultured cells, IFT139 relocalized along the extended microtubule network. We further showed that knockdown of IFT139 in podocytes leads to primary cilia defects, abnormal cell migration, and cytoskeleton alterations, which can be partially rescued by p.P209L overexpression, indicating its hypomorphic effect. Our results demonstrate the involvement of a ciliary gene in a glomerular disorder and point to a critical function of IFT139 in podocytes. Altogether, these data suggest that this homozygous TTC21B p.P209L mutation leads to a novel hereditary kidney disorder with both glomerular and tubulointerstitial damages.

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