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      Inheritance of a Stable Mutation in a Family with Early-Onset Disease


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          Autosomal/dominant polycystic kidney disease (ADPKD) exhibits a high inter- and intrafamilial heterogeneity partly explained by the involvement of at least 3 different genes in the disorder transmission. PKD1, the major locus, is located on chromosome 16p. The occurrence of very early-onset cases of ADPKD (sometimes in utero) in a few PKD1 families or the increased severity of the disease in successive generations raise the question of anticipation. This is a subject of controversial discussion. This report deals with the molecular analysis in families with very early-onset ADPKD. The finding of the same stable mutation with such different phenotypes rules out a dynamic mutation. The molecular basis of severe childhood PKD in typical ADPKD families remains unclear; it may include segregation of modifying genes or unidentified factors and the two-hit mechanism.

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          Most cited references12

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          The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I.

          Autosomal dominant polycystic kidney disease (ADPKD) is a common disease and an important cause of renal failure. It is characterized by considerable intrafamilial phenotypic variation and focal cyst formation. To elucidate the molecular basis for these observations, we have developed a novel method for isolating renal cystic epithelia from single cysts and have used it to show that individual renal cysts in ADPKD are monoclonal. Loss of heterozygosity was discovered within a subset of cysts for two closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. This study provides a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which "second hits" must occur to account for the large number of cysts observed suggests that unique structural features of the PKD1 gene may be responsible for its mutability.
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            Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.

            PKD1 and PKD2 are two recently identified genes that are responsible for the vast majority of autosomal polycystic kidney disease, a common inherited disease that causes progressive renal failure. PKD1 encodes polycystin, a large glycoprotein that contains several extracellular motifs indicative of a role in cell-cell or cell-matrix interactions, and the PKD2 encodes a protein with homology to a voltage-activated calcium channel and to PKD1. It is currently unknown how mutations of either protein functionally cause autosomal polycystic kidney disease. We show that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction resulted in an up-regulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 formed homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggest that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 may require the presence of PKD2 for stable expression.
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              Comparison of phenotypes of polycystic kidney disease types 1 and 2


                Author and article information

                S. Karger AG
                21 March 2001
                : 87
                : 4
                : 340-345
                Services de Néphrologie, aCHU Brest, bCH Saint-Brieuc, cService de Pédiatrie, CHU Brest, dLaboratoire de Génétique moléculaire, CHU Brest, France
                45940 Nephron 2001;87:340–345
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 52, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/45940
                Self URI (text/html): https://www.karger.com/Article/FullText/45940
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Anticipation – early onset of ADPKD,Phenotypic variability,Autosomal-dominant polycystic kidney disease


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