Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury observed either as an idiopathic finding or as a consequence of underlying systemic conditions. Several genes have been identified which, when mutated, lead to inherited FSGS and/or the nephrotic syndrome. These findings have accelerated the understanding of glomerular podocyte function and disease, motivating our search for additional FSGS genes. Using linkage analysis, we identified a locus for autosomal dominant FSGS on a region of chromosome 14q. By sequencing multiple genes in this region, we detected nine independent non-conservative missense mutations in INF2, which encodes a member of the formin family of actin regulating proteins. These mutations, all within the diaphanous inhibitory domain, segregate with disease in 11 unrelated families and alter highly conserved amino acid residues. The observation that mutations in this podocyte-expressed formin cause FSGS highlights the importance of fine regulation of actin polymerization in podocyte function.

Background: Focal and segmental glomerulosclerosis (FSGS) is the most common histologic pattern of renal injury seen in adults with idiopathic proteinuria. Homozygous or compound heterozygous mutations in the podocin gene NPHS2 are found in 10-30% of pediatric cases of steroid resistant nephrosis and/or FSGS.

The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the reninangiotensin-aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild type BALB/c mice after intravenous injection.We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was resequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells.Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

No abstract

The GAPF technique identifies palindromes associated with gene amplicons in cancers; however, the initial publication over stimated the frequency of palindrome formation and the frequency of palindromes occurring in similar locations among different cancers. The performance of the modified technique is discussed in the accompanying Correspondence 1 . In the version of this article initially published, the sentence under Table 1 on p. 1296 should stop after the words "and 430A arrays," and the words "or >3 if represented on only one array" should be removed. In addition, on p. 1298, the second parenthesis after "Tg(Hoxb7-myrVenus)" is missing. These errors have been corrected in the HTML and PDF versions of the article. c o r r i g e n d a a n d e r r ata nature genetics | volume 42 | number 4 | april 2010 361