FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.     

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.     

Natural products and plant disease resistance.

Plants elaborate a vast array of natural products, many of which have evolved to confer selective advantage against microbial attack. Recent advances in molecular technology, aided by the enormous power of large-scale genomics initiatives, are leading to a more complete understanding of the enzymatic machinery that underlies the often complex pathways of plant natural product biosynthesis. Meanwhile, genetic and reverse genetic approaches are providing evidence for the importance of natural products in host defence. Metabolic engineering of natural product pathways is now a feasible strategy for enhancement of plant disease resistance.     

A mutation in adenylosuccinate lyase associated with mental retardation and autistic features.

We have examined the molecular basis of three cases of severe mental retardation with autistic features in one family. A point mutation in a purine nucleotide biosynthetic enzyme, adenylosuccinate lyase (ASL), segregates with the disorder. The affected children are homozygous for the point mutation while the parents and all four unaffected children are heterozygous. The point mutation is absent in control subjects. The point mutation results in a Ser413Pro substitution which leads to structural instability of the recombinant mutant enzyme, and this instability lowers ASL levels in lymphocytes. These observations suggest that the instability of ASL underlies the severe developmental disorder in the affected children, and that mutations in the ASL gene may result in other cases of mental retardation and autistic features.     

The distribution of endocrine-like cells in the human male and female urethral epithelium

Summary Histochemical and electron microscopic techniques have been used to study the nature and distribution of fluorescent, endocrine-like cells in the urethra of the human male and female. The confinement of such cells to specific regions of the urethra is discussed in relation to the embryological development of this part of the urinary tract.     

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.     

A putative lipid transfer protein involved in systemic resistance signalling in Arabidopsis

Localized attack by a necrotizing pathogen induces systemic acquired resistance (SAR) to subsequent attack by a broad range of normally virulent pathogens. Salicylic acid accumulation is required for activation of local defenses, such as pathogenesis-related protein accumulation, at the initial site of attack, and for subsequent expression of SAR upon secondary, distant challenge. Although salicylic acid moves through the plant, it is apparently not an essential mobile signal. We screened Agrobacterium tumefaciens transfer DNA (tDNA) tagged lines of Arabidopsis thaliana for mutants specifically compromized in SAR. Here we show that Defective in induced resistance 1-1 (dir1-1) exhibits wild-type local resistance to avirulent and virulent Pseudomonas syringae, but that pathogenesis-related gene expression is abolished in uninoculated distant leaves and dir1-1 fails to develop SAR to virulent Pseudomonas or Peronospora parasitica. Petiole exudate experiments indicate that dir1-1 is defective in the production or transmission from the inoculated leaf of an essential mobile signal. DIR1 encodes a putative apoplastic lipid transfer protein and we propose that DIR1 interacts with a lipid-derived molecule to promote long distance signalling.     

Recycled dehydrated lithosphere observed in plume-influenced mid-ocean-ridge basalt

A substantial uncertainty in the Earth's global geochemical water cycle is the amount of water that enters the deep mantle through the subduction and recycling of hydrated oceanic lithosphere. Here we address the question of recycling of water into the deep mantle by characterizing the volatile contents of different mantle components as sampled by ocean island basalts and mid-ocean-ridge basalts. Although all mantle plume (ocean island) basalts seem to contain more water than mid-ocean-ridge basalts, we demonstrate that basalts associated with mantle plume components containing subducted lithosphere--'enriched-mantle' or 'EM-type' basalts--contain less water than those associated with a common mantle source. We interpret this depletion as indicating that water is extracted from the lithosphere during the subduction process, with greater than 92 per cent efficiency.