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. 2016 Feb 24;7:10822. doi: 10.1038/ncomms10822

Figure 1. FAT1 mutations cause a glomerulotubular nephropathy.

Figure 1

(a) Electron microscopy in A4623 with FAT1 mutation demonstrates the nephrotic syndrome (NS) feature of foot process effacement (arrowheads). Scale bar, 5 μm. (b) Renal histology of individual A4623 exhibits cystic dilation of renal tubules (hash), interstitial infiltrations (asterisks), and tubular basement membrane disruptions (arrowheads). Scale bar, 100 μm. (c) In A3507 with FAT1 mutation electron microscopy reveals the NS feature of extensive foot process effacement with microvilli formation (arrowheads). Scale bar, 5 μm. (d) Renal ultrasound of individual A3507 demonstrates loss of corticomedullary differentiation and increased echogenicity (L, liver). (e) Electron microscopy of A789 shows foot process effacement (arrowheads). Scale bar, 5 μm. (f) Renal histology of A789 shows tubulointerstitial infiltrates. Scale bar, 100 μm. (g) Homozygosity mapping identified 13 recessive candidate loci in individual A4623 with NS and tubular ectasia (TE). Non-parametric lod scores (NPL) were calculated and plotted across the human genome. The x-axis shows Affymetrix 250 K StyI array SNP positions on human chromosomes concatenated from p-ter (left) to q-ter (right). Genetic distance is given in cM. 13 maximum NPL peaks (red circles) indicate candidate regions of homozygosity by descent. The FAT1 locus (arrowhead) is positioned within the maximum NPL peak on chromosome 4q. (h) Exon structure of human FAT1 cDNA. FAT1 contains 27 exons. Positions of start codon (ATG) and of stop codon (TGA) are indicated. (i) Domain structure of FAT1. Protein domains are depicted by coloured bars in relation to encoding exon positions (h). FAT1 contains 33 cadherin domains (CA), a laminin G domain (LamG) and five epidermal growth factor (EGF)-like repeat domains (green bullets) in its extracellular region, followed by a transmembrane region (light blue bar) and a C-terminal cytoplasmic domain containing a PTB-like motif (red bar) with a PDZ-binding motif (-HTEV). (j) Two homozygous (H) and four different compound-heterozygous FAT1 mutations (h) detected in four families with a glomerulotubular nephropathy. Family numbers (underlined), mutations and predicted translational changes are indicated (see also Table 1).