Fig. 1.

High-throughput sequencing reveals recessive mutations of MAGI2, TNS2, DLC1, CDK20, ITSN1, or ITSN2 as causing NS in humans. a Renal histology of individual A5146-21 with focal segmental glomerulosclerosis (FSGS) and MAGI2 mutation (scale bar = 50 μm). b Exon structure of human MAGI2 cDNA and mutations. Below is the protein domain structure of MAGI2, showing GuK, WW1, WW2, and six different PDZ domains. Two different homozygous truncating mutations of MAGI2 were detected in two families with NS and neurological impairment. c Homozygosity mapping identifies ten recessive candidate loci (red circles) in family A1358 with NS, and WES identifies a homozygous mutation of TNS2 (p.Arg292Gln). Non-parametric lod scores (NPL) were calculated and plotted across the human genome. The TNS2 locus (arrowhead) is positioned within one of the maximum NPL peaks on chromosome 12q. d Exon and protein domain structure of human TNS2. Six different TNS2 mutations were detected in five families with NS. Family numbers and amino acid changes are given (Supplementary Table 1). Arrow heads denote altered nucleotides. Lines and arrows indicate positions of mutations in relation to exons and protein domains. Family numbers with compound heterozygous mutations (het) are highlighted in gray. e Renal histology of individual A4967-21 with FSGS and DLC1 mutations. TEM reveals podocyte foot process effacement (arrow heads, magnification 8000x). f Exon and protein domain structure of human DLC1. The SAM, RhoGAP, and START domains are depicted by colored bars, in relation to encoding exon position. Six different DLC1 mutations were detected in four families with NS. Positions of amino acid changes (Supplementary Table 1) are marked with arrowheads. g Renal histology of individual A5013-21 with membranoproliferative glomerulonephritis (MPGN) and mutation in CDK20. TEM reveals podocyte foot process effacement and thickening of glomerular basement membrane (arrow heads, magnification 7000x). h Homozygosity mapping identifies twelve recessive candidate loci (red circles) in family A5013 with NS, and WES identifies a homozygous mutation of CDK20 (p.Phe204Leu), positioned within one of the maximum NPL peaks on chromosome 9q. i Exon and protein domain structure of human CDK20. The serine threonine kinase (S_TKc) domain is depicted by a colored bar, in relation to encoding exon position. One homozygous mutation in CDK20 was detected in family A5013 with NS. j Homozygosity mapping in family A3706 with NS identifies 17 recessive candidate loci (red circles), and WES identifies a homozygous mutation of ITSN1 (p.Pro180Ser), positioned within one of the maximum NPL peaks on chromosome 21q. k Exon and protein domain structure of human ITSN1. Five different ITSN1 mutations were detected in three families with NS. l Renal histology of Patient-1 with mutations in ITSN2 revealed minimal change disease (scale bar = 50 μm). EM showed foot process effacement (scale bar = 2 μm). m Exon and protein domain structure of human ITSN2. Three different ITSN2 mutations were detected in two families with NS