ABSTRACT
BACKGROUND: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. METHODS: To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping. RESULTS: The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis. CONCLUSIONS: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.
Subject(s)
Kidney Diseases, Cystic/genetics , Liver Cirrhosis/genetics , Membrane Proteins/genetics , Cohort Studies , Consanguinity , Haplotypes , Homozygote , Humans , Kidney Diseases, Cystic/complications , Liver Cirrhosis/complications , Lod Score , Mutation, Missense , Oligonucleotide Array Sequence Analysis , Pedigree , Polymorphism, Single NucleotideABSTRACT
Thiocyanate is present in appreciable concentration in coal carbonization wastewater along with other toxicants like phenols, cyanide, sulphide and ammonia. This paper encompasses studies on biodegradation of thiocyanate by a microbial consortium obtained from a biological treatment plant receiving coal carbonization wastewater. Effects of secondary toxicants and growth stimulants on thiocyanate oxidation by the consortium, and thiocyanate transformation in actual and partially treated coal carbonization waste, have also been studied. Results indicate that the consortium can degrade thiocyanate up to 1400 mg litre(-1) in batch culture with 10 mg litre(-1) of initial inoculum within a period of 6 days. Phenol above 500 mg litre(-1) and cyanide at 10 mg litre(-1) completely inhibits thiocyanate oxidation. Sulphide at 32 mg litre(-1) and ammonia at 4000 mg litre(-1) at neutral pH prolongs thiocyanate oxidation from 3 to 6 days and from 4 to 7.5 days, respectively. These studies reveal that elimination of phenolics, their oxidized products, ammonia, cyanides and sulphides is a pre-requisite for effective thiocyanate removal from the waste by the consortium. Bacteria of the genera Pseudomonas and Bacillus dominate the consortium.
