Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians.We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing.We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls.We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.
Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.
The aim was to evaluate the organoleptic quality of drinking water conducted in asbestos cement piping, in eleven towns in the Marche region (Italy) and the presence of asbestos fibres. A descriptive survey was also conducted to assess possible health effects in the population, in particular morbidity and mortality due to gastrointestinal (GI) cancer. Study results show a very low concentration of free asbestos fibres in water samples examined. No differences in mortality and morbidity due to GI cancers were detected compared to the national population.
ABSTRACT. The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5′ region had significantly more severe disease than the 3′ group; median time to ESRD was 53 and 56 yr, respectively ( P = 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.
Journal Article Single base pair deletions in exons 39 and 42 of the COL4A5 gene in Alport syndrome Get access Alessandra Renieri, Alessandra Renieri * *To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Lucia Galli, Lucia Galli Search for other works by this author on: Oxford Academic PubMed Google Scholar Mario De Marchl, Mario De Marchl 1Dipartimento di Scienze Cliniche e Biologiche, Università di Torino10034 Orbassano Search for other works by this author on: Oxford Academic PubMed Google Scholar Florindo Mollica, Florindo Mollica 2Clinica Pediatrica, Università di CataniaCatania Search for other works by this author on: Oxford Academic PubMed Google Scholar Antonio Lupo, Antonio Lupo 3Divisione di Nefrologia Medica Search for other works by this author on: Oxford Academic PubMed Google Scholar Giuseppe Maschio, Giuseppe Maschio 3Divisione di Nefrologia Medica Search for other works by this author on: Oxford Academic PubMed Google Scholar Bernard Peissel, Bernard Peissel 4Istituto di Scienze Biologiche e Genetica, Università di VeronaVerona 37134, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Sandro Rossetti, Sandro Rossetti 4Istituto di Scienze Biologiche e Genetica, Università di VeronaVerona 37134, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Pierfranco Pignatti, Pierfranco Pignatti 4Istituto di Scienze Biologiche e Genetica, Università di VeronaVerona 37134, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Alberto E.Turco Alberto E.Turco 4Istituto di Scienze Biologiche e Genetica, Università di VeronaVerona 37134, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 3, Issue 1, January 1994, Pages 201–202, https://doi.org/10.1093/hmg/3.1.201 Published: 01 January 1994 Article history Received: 17 September 1993 Accepted: 11 November 1993 Published: 01 January 1994
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