An expanding universe of FSGS genes and phenotypes: LMX1B mutations cause familial autosomal dominant FSGS lacking extrarenal manifestations.

At present, there are 24 genes associated with FSGS that follow Mendelian patterns of inheritance. These patterns of inheritance include autosomal recessive, autosomal dominant, and X-linked as well as inheritance of mitochondrial DNA. The phenotypes include syndromic FSGS, in which manifestations occur in other tissues, and nonsyndromic FSGS, in which disease is limited to the kidney. The list of FSGS genes continues to lengthen, and in this age of whole-exome scans, it is likely to expand considerably in the next few years. To date, all of the FSGS genes are expressed in the podocytes, but they are rarely specific to the podocyte; this finding constitutes part of the evidence that FSGS is a podocytopathy. The FSGS genes can be classified according to the cellular organelle or activity where the gene product plays a particularly notable role. These organelle/activity clusters include the following clusters: cell/extracellular matrix (ITGB4 and LAMB2), slit diaphragm components or interacting proteins (NPHS1,NPHS2,CD2AP, PTPRO, andMYO1E), cytokseleton (ACTN4, INF2, MYH9, ARHGAP24, and ARHGDIA), mitochondria function (IN2F, tRNA-Leu, COQ2, COQ6, and PDSS2), DNA repair/transcription (WT1, NEIL1, LMX1B, SMARCAL1, and NXF5), cell signaling (PLCE1 and TRPC6), and lysosome (SCARB2). IFN2 appears in two functional groups, and therefore, this list totals 25 genes. Some genes are reported to cause only nonsyndromic FSGS, other genes are reported to cause only syndromic FSGS, and others may cause both syndromic and nonsyndromic FSGS (e.g., INF2 andWT1). The current issue of JASN adds LMX1B to this list of switch-hitting genes that may cause both syndromic and nonsyndromic FSGS. Boyer andWerner (1) studied an extended pedigree with autosomal dominant FSGS but lacking extrarenal manifestations. LMX1B encodes the Lin-11, Isi-1, andMec3 (LIM) homeodomain 1 b-transcription factor. The protein possesses two LIM domains (each with two zinc finger domains involved in protein–protein interactions; e.g., with E47 and LDB1 [NL1 and CLIM2]) at the amino terminus and a homeodomain involved in DNA binding (to a defined FLAT element in gene enhancers) in the middle portion of the molecule. LMX1B mutations associated with nail patella syndrome are clustered in the LIM andDNAbinding domains, underscoring the functional importance of these domains (2). LMX1B is a dorsoventral regulator in development, determining cell motility during limb formation as well as contributing to development of the calvaria, anterior elements of the eyes, and neurons in the central nervous systems and podocyte maturation (3). Lmx1b expression begins in the mouse kidney at embryonic day 14.5, because the visceral epithelium is undergoing differentiation into podocytes, and expression persists throughout embryonic development and adult life. Lmx1b knockout mice manifest several features indicating impaired podocyte differentiation and diminished podocyte production of collagen IV a3 and collagen IV a4 chains. The pathways that are downstream of LMX1B are complex, including the following genes: (1) genes that control laminin gene expression, at least in the spinal cord (4); (2) podocyte genes with products that include nephrin, podocin (5), CD2AP, and collagen IV chains; (3) Wnt and Pax family genes involved in cell survival; (4) genes involved in 5-hydroxytryptamine synthesis and function; and (5) inflammation-associated genes, including IL-6 and IL-8, leading to NF-kB activation. Although these genes constitute a diverse set of pathways, they suggest the specific ways in which LMX1B may be critical to optimal podocyte function under various physiologic and pathologic situations. The nail patella syndrome is an autosomal dominant conditionwith a pleiotropic phenotype and a long history. Cases werefirst described in 1897, familial and sporadic formswere described in 1912, autosomal dominant inheritance was described in 1933, and linkage to the ABO blood group was made by Renwick in 1955. The syndrome was finally attributed to LMX1B mutations in 1998 by Dreyer, who noted similarity to Lmx1B knockout mice; this attribution was arrived at independently by Vollrath (this interesting investigative history is reviewed by McIntosh et al. [6]). Limb abnormalities include a diagnostic tetrad: dysplasia of patellas, nails, and Published online ahead of print. Publication date available at www.jasn.org.