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2.
J Am Soc Nephrol ; 17(5): 1429-36, 2006 May.
Article in English | MEDLINE | ID: mdl-16611713

ABSTRACT

Autosomal dominant pseudohypoaldosteronism type 1 (adPHA1) is a rare condition that is characterized by renal resistance to aldosterone, with salt wasting, hyperkalemia, and metabolic acidosis. It is thought of as a mild disorder; affected children's symptoms respond promptly to salt therapy, and treatment is not required after childhood. Mutations in the mineralocorticoid receptor gene (MR) cause adPHA1, but the long-term consequences of MR deficiency in humans are not known. Herein are described six novel adPHA1-causing MR mutations (four de novo) and evidence that haploinsufficiency of MR is sufficient to cause adPHA1. Furthermore, genotype-phenotype correlation is reported in a large adPHA1 kindred. A number of cases of neonatal mortality in infants who were at risk for adPHA1 were identified; coupled with the frequent identification of de novo mutations in affected individuals, this suggests that the seemingly benign adPHA1 may have been a fatal neonatal disorder in previous eras, preventing propagation of disease alleles. In contrast, it is shown that adult patients with adPHA1 are clinically indistinguishable from their wild-type relatives except for presumably lifelong elevation of renin, angiotensin II, and aldosterone levels. These data highlight the critical role of MR in the maintenance of salt homeostasis early in life and illuminate the sodium dependence of pathologic effects of renin and angiotensin II. They furthermore argue that nongenomic effects of aldosterone play no significant role in the long-term development of cardiovascular disease.


Subject(s)
Pseudohypoaldosteronism/epidemiology , Pseudohypoaldosteronism/genetics , Receptors, Mineralocorticoid/genetics , Risk Assessment/methods , Adult , Evidence-Based Medicine , Female , Gene Expression , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Heterozygote , Humans , Incidence , Infant , Infant Mortality , Male , Phenotype , Pseudohypoaldosteronism/metabolism , Risk Factors , Spain/epidemiology
3.
Nat Genet ; 36(6): 575-7, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15133510

ABSTRACT

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.


Subject(s)
Membrane Proteins/genetics , Mutation , Polycystic Kidney, Autosomal Dominant/genetics , Chromosomes, Human, Pair 6/genetics , DNA Mutational Analysis , Endoplasmic Reticulum/metabolism , Humans , Molecular Chaperones , Protein Processing, Post-Translational , RNA-Binding Proteins
4.
Hum Mutat ; 23(5): 453-63, 2004 May.
Article in English | MEDLINE | ID: mdl-15108277

ABSTRACT

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality. The clinical spectrum is widely variable. About 30 to 50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, which is among the largest human genes, with a minimum of 86 exons assembled into a variety of alternatively spliced transcripts. The longest continuous open reading frame is predicted to yield a 4,074-aa (447-kDa) multidomain integral membrane protein (fibrocystin/polyductin) of unknown function. This update compiles all known PKHD1 mutations and polymorphisms/sequence variants. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Most PKHD1 mutations are unique to single families ("private mutations") hampering genotype-phenotype correlations. Correlations have been drawn for the type of mutation rather than for the site of individual mutations. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise, while patients surviving the neonatal period bear at least one missense mutation. However, some missense changes are obviously as devastating as truncating mutations. The present article intends 1) to provide an overview of PKHD1 mutations and polymorphisms/sequence variants identified so far, 2) to discuss potential genotype-phenotype correlations, and 3) to review them in the context of their clinical implications. A constantly updated list of mutations is available online (www.humgen.rwth-aachen.de) and investigators are invited to submit their novel data to this PKHD1 mutation database.


Subject(s)
Mutation , Polycystic Kidney, Autosomal Recessive/genetics , Receptors, Cell Surface/genetics , DNA Mutational Analysis/trends , Genetic Variation , Genotype , Haplotypes , Humans , Molecular Sequence Data , Phenotype , Polycystic Kidney, Autosomal Recessive/diagnosis , Polycystic Kidney, Autosomal Recessive/pathology , Polymorphism, Genetic , RNA Splicing , Receptors, Cell Surface/metabolism
5.
J Am Soc Nephrol ; 14(8): 2004-14, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12874454

ABSTRACT

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a hereditary and severe form of polycystic disease affecting the kidneys and biliary tract with an estimated incidence of 1 in 20,000 live births. The clinical spectrum is widely variable: up to 50% of affected neonates die shortly after birth, whereas others survive to adulthood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1), are responsible for all typical forms of ARPKD. Mutation detection was performed in PKHD1 by DHPLC in 85 affected, unrelated individuals. Seventy-four amplicons were amplified and analyzed from the PKHD1 genomic locus. Sequence variants were considered pathogenic when they were not observed in 160 control individuals (320 chromosomes). For purposes of genotype-phenotype comparisons, families were stratified by clinical presentation into two groups: the severe perinatal group, in which at least one affected child presented with perinatal disease and neonatal demise, and the less severe, nonperinatal group, in which none of the affected children died in the neonatal period. Forty-one mutations were found in 55 affected disease chromosomes; 32 of these mutations have not been reported previously. Mutations were distributed throughout the portions of gene encoding the predicted extracellular portion of the protein product. The most commonly encountered mutation, T36M, was found in 8 of 55 disease chromosomes. Amino acid substitutions were found to be more commonly associated with a nonlethal presentation, whereas chain terminating mutations were more commonly associated with neonatal demise (chi(2) = 11.54, P = 0.003). All patients who survive the neonatal period have at least one amino acid substitution mutation, suggesting that such substitutions produce milder disease through production of partially functional protein products. The nature of the germline mutations in ARPKD plays a significant role in determining clinical outcome.


Subject(s)
Genes, Recessive , Mutation , Polycystic Kidney Diseases/genetics , Receptors, Cell Surface/genetics , Amino Acids , Child , Child, Preschool , DNA Mutational Analysis , DNA Primers/chemistry , Exons , Genotype , Heterozygote , Humans , Infant , Infant, Newborn , Models, Genetic , Phenotype , Polymorphism, Genetic , Prognosis , Protein Structure, Tertiary , Receptors, Cell Surface/chemistry , Time Factors , Treatment Outcome
6.
Am J Hum Genet ; 72(3): 691-703, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12529853

ABSTRACT

Autosomal dominant polycystic liver disease (ADPLD) is a distinct clinical and genetic entity that can occur independently from autosomal dominant polycystic kidney disease (ADPKD). We previously studied two large kindreds and reported localization of a gene for ADPLD to an approximately 8-Mb region, flanked by markers D19S586/D19S583 and D19S593/D19S579, on chromosome 19p13.2-13.1. Expansion of these kindreds and identification of an additional family allowed us to define flanking markers CA267 and CA048 in an approximately 3-Mb region containing >70 candidate genes. We used a combination of denaturing high-performance liquid chromatography (DHPLC) heteroduplex analysis and direct sequencing to screen a panel of 15 unrelated affected individuals for mutations in genes from this interval. We found sequence variations in a known gene, PRKCSH, that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations. In contrast to PKD1, PKD2, and PKHD1, PRKCSH encodes a previously described human protein termed "protein kinase C substrate 80K-H" or "noncatalytic beta-subunit of glucosidase II." This protein is highly conserved, is expressed in all tissues tested, and contains a leader sequence, an LDLa domain, two EF-hand domains, and a conserved C-terminal HDEL sequence. Its function may be dependent on calcium binding, and its putative actions include the regulation of N-glycosylation of proteins and signal transduction via fibroblast growth-factor receptor. In light of the focal nature of liver cysts in ADPLD, the apparent loss-of-function mutations in PRKCSH, and the two-hit mechanism operational in dominant polycystic kidney disease, ADPLD may also occur by a two-hit mechanism.


Subject(s)
Chromosomes, Human, Pair 19 , Cysts/genetics , Intracellular Signaling Peptides and Proteins , Liver Diseases/genetics , Membrane Proteins , Mutation , Phosphoproteins/genetics , Alternative Splicing , Amino Acid Sequence , Amino Acid Substitution , Base Sequence , Calcium-Binding Proteins , Chromosome Mapping , DNA/blood , DNA/genetics , Female , Genes, Dominant , Genetic Linkage , Genetic Markers , Glucosidases , Haplotypes , Humans , Male , Molecular Sequence Data , Myristoylated Alanine-Rich C Kinase Substrate , Pedigree , Phosphoproteins/metabolism , Point Mutation , Polycystic Kidney, Autosomal Dominant/genetics , Protein Kinase C/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Alignment , Sequence Homology, Amino Acid
7.
J Am Soc Nephrol ; 14(1): 76-89, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12506140

ABSTRACT

Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074-amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges.


Subject(s)
Polycystic Kidney, Autosomal Recessive/genetics , Receptors, Cell Surface/genetics , Adolescent , Adult , Alleles , Base Sequence , Child , Child, Preschool , Chromosomes, Human, Pair 6/genetics , Cohort Studies , DNA Mutational Analysis , Female , Genetic Testing , Genotype , Humans , Infant , Male , Molecular Sequence Data , Mutation , Mutation, Missense , Open Reading Frames , Pedigree , Phenotype
8.
J Am Soc Nephrol ; 13(9): 2246-58, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12191969

ABSTRACT

PKHD1, the gene mutated in human autosomal recessive polycystic kidney disease has recently been identified. Its translation products are predicted to belong to a superfamily of proteins involved in the regulation of cellular adhesion and repulsion. One notable aspect of the gene is its unusually complex pattern of splicing. This study shows that mouse Pkhd1 and its translation products have very similar properties to its human orthologue. Mouse Pkhd1 extends over approximately 500 kb of genomic DNA, includes a minimum of 68 nonoverlapping exons, and exhibits a complex pattern of splicing. The longest ORF encodes a protein of 4059aa predicted to have an N-terminal signal peptide, multiple IPTs and PbH1 repeats, a single transmembrane span (TM), and a short cytoplasmic C-terminus. Although the protein sequence is generally well conserved (approximately 73% average identity), the C-termini share only 55% identity. The pattern of Pkhd1 expression by in situ hybridization was also examined in developing and adult mouse tissues over a range of ages (E12.5 to 3 mo postnatal). High levels of expression were present in renal and biliary tubular structures at all time points examined. Prominent Pkhd1 signals were also found in a number of other organs and tissues. Tissue-specific differences in transcript expression were revealed through the use of single exon probes. These data show that key features of human PKHD1 are highly conserved in the mouse and suggest that the complicated pattern of splicing is likely to be functionally important.


Subject(s)
Kidney Tubules/physiology , Proteins/genetics , Receptors, Cell Surface/genetics , Animals , Exons/genetics , Gene Expression Regulation, Developmental , Genomics , Humans , In Situ Hybridization , Kidney Tubules/embryology , Mice , Molecular Sequence Data , RNA Splicing/genetics , RNA, Messenger/analysis , TRPP Cation Channels
9.
Am J Med Genet ; 110(4): 346-52, 2002 Jul 15.
Article in English | MEDLINE | ID: mdl-12116208

ABSTRACT

Autosomal recessive polycystic kidney disease (ARPKD) is an often devastating form of polycystic kidney disease that presents primarily in infancy. The locus, PKHD1 (polycystic kidney and hepatic disease 1), on chromosome 6p21.1-p12, has been linked to all classical forms of this disorder. In previous studies, we cloned the PKHD1 interval in a set of overlapping YACs, converted this YAC-based framework into a BAC/PAC contig, and delimited the critical interval to a region flanked by the markers D6S1714 and D6S1024. We now have refined the genetic interval using new polymorphic markers developed from our BAC/PAC resources. In addition, we have evaluated a recently identified, EF hand-containing gene that maps to the interval of interest, established its transcript sequence, defined its genomic organization, and excluded this new gene as a PKHD1 candidate. Therefore, this study has narrowed the PKHD1 interval and excluded a potentially relevant gene as a PKHD1 candidate gene. This further refinement of the PKHD1 interval will facilitate efforts to identify the PKHD1 gene by positional cloning. These data also provide additional, highly polymorphic markers for haplotype-based diagnostic testing for ARPKD.


Subject(s)
Polycystic Kidney, Autosomal Recessive/genetics , Receptors, Cell Surface/genetics , Amino Acid Sequence , Base Sequence , Blotting, Northern , Chromosome Mapping , Chromosomes, Human, Pair 6/genetics , Female , Gene Expression , Genetic Predisposition to Disease/genetics , Humans , Male , Microsatellite Repeats , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism
10.
Am J Hum Genet ; 70(5): 1305-17, 2002 May.
Article in English | MEDLINE | ID: mdl-11898128

ABSTRACT

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease that presents primarily in infancy and childhood and that is characterized by enlarged kidneys and congenital hepatic fibrosis. We have identified PKHD1, the gene mutated in ARPKD. PKHD1 extends over > or =469 kb, is primarily expressed in human fetal and adult kidney, and includes a minimum of 86 exons that are variably assembled into a number of alternatively spliced transcripts. The longest continuous open reading frame encodes a 4,074-amino-acid protein, polyductin, that is predicted to have a single transmembrane (TM)-spanning domain near its carboxyl terminus, immunoglobulin-like plexin-transcription-factor domains, and parallel beta-helix 1 repeats in its amino terminus. Several transcripts encode truncated products that lack the TM and that may be secreted if translated. The PKHD1-gene products are members of a novel class of proteins that share structural features with hepatocyte growth-factor receptor and plexins and that belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion.


Subject(s)
Cell Adhesion Molecules/chemistry , Immunoglobulins/chemistry , Nerve Tissue Proteins/chemistry , Polycystic Kidney, Autosomal Recessive/genetics , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/genetics , Age of Onset , Alternative Splicing/genetics , Amino Acid Motifs , Base Sequence , Chromosomes, Human, Pair 6/genetics , DNA Mutational Analysis , Exons/genetics , Female , Fetus/metabolism , Gene Expression Profiling , Gene Expression Regulation, Developmental , Humans , Kidney/metabolism , Male , Molecular Sequence Data , Pedigree , Polycystic Kidney, Autosomal Recessive/epidemiology , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Transport , RNA, Messenger/genetics , RNA, Messenger/metabolism
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