A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family

Turco, Alberto; Rossetti, Sandro; Bresin, Elena; Corrà, Stefano; Gammaro, Linda; Maschio, Giuseppe; Pignatti, Pier Franco

doi:10.1093/hmg/4.8.1331

Cited by 55 publications

(43 citation statements)

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“…Four nonsense mutations were identified, two each in PKD1 and PKD2 . Among them, a 50905 C→T mutation in PKD1 and a 2407 C→T substitution in PKD2 has once been reported [16, 23, 24, 25]. A representative example is seen in figure 6, which depicts a 2407 C→T PKD2 mutation in pedigree H3.…”

Section: Resultsmentioning

confidence: 99%

Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

Zhang¹,

Mei²,

Zhang³

et al. 2005

Nephron Exp Nephrol

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2. The complexity of these genes, particularly PKD1, has complicated genetic screening, though recent advances have provided new opportunities for amplifying these genes. In the Han Chinese population, no complete mutational analysis has previously been conducted across the entire span of PKD1 and PKD2. Here, we used single-strand conformation polymorphism (SSCP) analysis to screen the entire coding sequence of PKD1 and PKD2 in 85 healthy controls and 72 Han Chinese from 24 ADPKD pedigrees. In addition to 11 normal variants, we identified 17 mutations (12 in PKD1 and 5 in PKD2), 15 of which were novel ones (11 for PKD1 and 4 for PKD2). We did not identify any seeming mutational hot spots in PKD1 and PKD2. Notably, we found several disease-associated C–T or G–A mutations that led to charge or hydrophobicity changes in the corresponding amino acids. This suggests that the mutations cause conformational alterations in the PKD1 and PKD2 protein products that may impact the normal protein functions. Our study is the first report of screenable mutations in the full-length PKD1 and PKD2 genes of the Han Chinese, and also offers a benchmark for comparisons between Caucasian and Han ADPKD pedigrees and patients.

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Section: Resultsmentioning

confidence: 99%

Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

Zhang¹,

Mei²,

Zhang³

et al. 2005

Nephron Exp Nephrol

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“…If polycystin molecules normally interact, this may occur if PKD1 mutations generate an aberrant protein which binds the normal product and creates a nonfunctional complex. Analyses of the limited number of mutations described so far do show examples of changes in the 3' end of PKDJ (10,29,30) which may make an abnormal product with a defective C-terminal region. However, there is also evidence that null mutations (but which also disrupt the adjacent TSC2 gene) cause polycystic kidney disease (31), suggesting that a shortage of polycystin may be enough to trigger the cascade leading to cyst development.…”

Section: Discussionmentioning

confidence: 98%

Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.

Ward

Turley

Ong

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

239

157

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Polycystic kidney disease 1 (PKDI) is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease. We have studied PKDI mRNA, with an RNase protection assay, and found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein, polycystin, was assessed in kidney using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining is restricted to epithelial cells. Expression in the developing nephron is most prominent in mature tubules, with lesser staining in Bowman's capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal was observed in comma-and S-shaped bodies as well as the distal branches of the ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no staining. In later fetal (>20 weeks) and adult kidney, strong staining persists in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. These results suggest that polycystin's major role is in the maintenance of renal epithelial differentiation and organization from early fetal life. Interestingly, polycystin expression, monitored at the mRNA level and by immunohistochemistry, appears higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein.

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“…Because of the size of the PKD1 gene we have not, as yet, determined the nature of the mutations in these patients. Nevertheless, to date, no two unrelated ADPKD patients have been reported to carry the same PKD1 mutation so that these 15 kidneys are likely to represent a range of different mutations (16)(17)(18)(19). Therefore, overexpression of polycystin in cysts appears to be a general property of ADPKD rather than a specific feature of a particular mutation.…”

Section: Discussionmentioning

confidence: 99%

Identification and localization of polycystin, the PKD1 gene product.

Geng¹,

Segal²,

Peissel³

et al. 1996

J. Clin. Invest.

191

154

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Polycystin, the product of autosomal dominant polycystic kidney disease (ADPKD) 1 gene ( PKD1 ) is the cardinal member of a novel class of proteins. As a first step towards elucidating the function of polycystin and the pathogenesis of ADPKD, three types of information were collected in the current study: the subcellular localization of polycystin, the spatial and temporal distribution of the protein within normal tissues and the effects of ADPKD mutations on the pattern of expression in affected tissues. Antisera directed against a synthetic peptide and two recombinant proteins of different domains of polycystin revealed the presence of an ‫ف‬ 400-kD protein (polycystin) in the membrane fractions of normal fetal, adult, and ADPKD kidneys. Immunohistological studies localized polycystin to renal tubular epithelia, hepatic bile ductules, and pancreatic ducts, all sites of cystic changes in ADPKD, as well as in tissues such as skin that are not known to be affected in ADPKD. By electron microscopy, polycystin was predominantly associated with plasma membranes. Polycystin was significantly less abundant in adult than in fetal epithelia. In contrast, polycystin was overexpressed in most, but not all, cysts in ADPKD kidneys. ( J. Clin. Invest. 1996. 98:2674-2682.)

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A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family

Cited by 55 publications

References 0 publications

Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.

Identification and localization of polycystin, the PKD1 gene product.

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