Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the major hereditary nephropathies in children predominantly presenting in early childhood. The clinical picture is variable but there is a fatal outcome in many cases. We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes. Linkage was confirmed using six adjacent microsatellite markers and the highest lod score of 7.42 was obtained with D6S272 at theta = 0.00. Our findings should lead to more accurate forms of prenatal diagnosis than those currently available using ultrasound.

Autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disorder which usually becomes clinically manifest in early childhood, although the spectrum of ARPKD is much more variable than generally known. Presentation of ARPKD at later ages and survival into adulthood have been observed in many cases. The responsible gene has been mapped to chromosome 6p. Thus there is no evidence of genetic heterogeneity. The most important indication for DNA diagnosis is the prenatal diagnosis in families with at least one affected child. The critical region has been narrowed with the use of recombinant families of about 4 cM. Several possible candidate genes have been excluded.

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p.

We report on two sibs, both males, one born at 37 the other at 24 weeks of gestation, both with a syndrome similar to that seen in three sets of sibs by Gillessen-Kaesbach et al. [1993: Am J Med Genet 45:511-518]. Both propositi had polycystic kidneys and hepatic fibrosis indistinguishable from that seen in autosomal recessive polycystic kidney disease (ARPKD), and skeletal and facial anomalies. Skeletal abnormalities included "butterfly" vertebrae, square shape of pelvis, and brachymelia. The facial anomalies included hypertelorism, epicanthic folds, and anteverted nares. Additional external findings were apparently low-set ears and a short neck. Histopathological examination of the kidneys showed radial orientation and cystic dilatation of the cortical and medullar tubules. The liver showed "congenital hepatic fibrosis." The hepatic findings in the second infant were less severe. Renal abnormalities were limited to focal tubular cystic changes. Linkage analysis with polymorphic markers of the region 6p21.1-p12, flanking the gene locus of ARPKD, showed different haplotypes in the sibs, thus excluding the ARPKD gene locus in this family and indicating genetic heterogeneity.

Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases and has a high infant mortality. Prenatal diagnosis using fetal sonography can be unreliable, especially in early pregnancy. The ARPKD locus has been mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in "at-risk" families. From December 1994 to March 1997, we received 258 inquiries regarding prenatal evaluation and we have completed analyses in 212 families. To date, 65 prenatal analyses have been performed in 57 families. In the majority of the requesting families (45/57), the index children are deceased and their DNA was extracted from paraffin-embedded tissue. Eighteen fetuses were homozygous for the disease-associated haplotypes. In 12 of these fetuses, pathoanatomical examination demonstrated typical ARPKD changes consisting of dilated collecting ducts and the characteristic hepatic ductal plate malformation. These changes were detected in two fetuses as early as 13 weeks gestational age. These cases represent the earliest demonstration of ARPKD-associated histopathology reported to date. One high risk fetus was carried to term and turned out to be unaffected. However, the diagnosis of ARPKD remained doubtful in the index patient. Forty-three fetuses were either heterozygous or homozygous for a nondisease-associated haplotype and all infants born were phenotypically unaffected at birth. In four cases, a recombination event occurred between the flanking markers and no genotypic prediction was possible. Three of these pregnancies were terminated and necropsy of the fetuses confirmed ARPKD, while one fetus was carried to term and showed no abnormalities at birth. These results show that haplotype-based prenatal testing is feasible and reliable in pregnancies "at risk" for ARPKD. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in previously affected sib(s).

Autosomal recessive polycystic kidney disease: mapping to chromosomal region of 6p21-cen in a Turkish child.

Autosomal recessive polycystic kidney disease (ARPCD) is a congenital kidney disease with severe prognosis. We present a male infant who was diagnosed prenatally by ultrasonography. He died at two months of age in a septic stage. The genetic defect for ARPCD has been mapped to chromosomal region of 6p21-cen. This represents the first study from this region of the world. The linkage studies up to this date fall to show genetic heterogeneity.

Autosomal recessive polycystic kidney disease does not map to the second gene locus for autosomal dominant polycystic kidney disease on chromosome 4.

Linkage analysis in 19 families with autosomal recessive polycystic kidney disease (ARPKD) has shown that ARPKD is not linked to the recently assigned second gene locus for autosomal dominant polycystic kidney disease (ADPKD) on chromosome 4q (PKD2). Thus, there is strong evidence that ADPKD and ARPKD have different gene loci.

A HhaI polymorphism in the human MEP1A gene encoding the alpha subunit of the metalloendopeptidase meprin.

Meprins are membrane-bound oligomeric metalloendopeptidases belonging to the astacin protein family. The meprin isolated from human small intestinal mucosa was originally known as N-benzoyl-L-tyrosyl-p-aminobenzoic acid (PABA peptide) hydrolase (PPH). Here we describe the first genetic marker for the human MEP1A gene encoding the alpha subunit of this enzyme. The polymorphism changes codon 176 of the mature alpha chain of PPH from CAA to CAG. Using the polymerase chain reaction, this variation is easily detectable as a HhaI restriction fragment length polymorphism. The two alleles are both common, probably in all major races.

Autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disorder which usually becomes clinically manifest in early childhood. With increasing knowledge and improving diagnostic techniques it has become evident that the spectrum of ARPKD is much more variable than was previously thought. Presentation of ARPKD at later ages and survival into adulthood is well known. Diagnostic criteria, clinical course, genetics and differential diagnosis of ARPKD are presented.

Fine mapping of MEP1A, the gene encoding the alpha subunit of the metalloendopeptidase meprin, to human chromosome 6P21.

Meprins are kidney and intestinal proteases encoded by two distinct genes, MEP1A and MEP1B. MEP1A was previously mapped to human chromosome 6p, by the use of radiation and somatic cell hybrids, in the region containing the gene for autosomal recessive polycystic kidney disease (ARPKD). We now report the fine mapping of MEP1A using yeast artificial chromosome clones, and linkage analysis of ARPKD families. The results from both physical and genetic mapping exclude MEP1A as a candidate for ARPKD. These studies place MEP1A in a region more telomeric to 6p12 and closer to the HLA loci than previously reported. More specifically, MEP1A is localized between loci D6S272 and D6S282, close to D6S452, on human chromosome 6p21.2-p21.1. The more precise location of MEP1A will facilitate genetic studies of this locus and clarify the relation of this gene to others.

Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta.

Expression of AP-2 transcription factors has been detected previously in embryonic renal tissues. We show here that AP-2beta -/- mice complete embryonic development and die at postnatal days 1 and 2 because of polycystic kidney disease. Analyses of kidney development revealed that induction of epithelial conversion, mesenchyme condensation, and further glomerular and tubular differentiation occur normally in AP-2beta-deficient mice. At the end of embryonic development expression of bcl-X(L), bcl-w, and bcl-2 is down-regulated in parallel to massive apoptotic death of collecting duct and distal tubular epithelia. Addressing the molecular mechanism we show that transfection of AP-2 into cell lines in vitro strongly suppresses c-myc-induced apoptosis pointing to a function of AP-2 in programming cell survival during embryogenesis. The position of the human AP-2beta gene was identified at chromosome 6p12-p21.1, within a region that has been mapped for autosomal recessive polycystic kidney disease (ARPKD). Sequence analyses of ARPKD patients and linkage analyses using intragenic polymorphic markers indicate that the AP-2beta gene is located in close proximity to but distinct from the ARPKD gene.

Fine mapping of the autosomal recessive polycystic kidney disease locus (PKHD1) and the genes MUT, RDS, CSNK2 beta, and GSTA1 at 6p21.1-p12.

A total of 33 polymorphic markers were analyzed to generate a high-resolution genetic linkage map of the locus PKHD1 (polycystic kidney and hepatic disease 1) for the autosomal recessive polycystic kidney disease (ARPKD), using a combination of recombination mapping and linkage analysis in 164 families. Recombinants narrowed the PKHD1 region from 3.8 cM to a 1-cM interval flanked by the markers D6S1024 and D6S1714. Linkage disequilibrium analysis in 13 Finnish ARPKD families identified two different highly conserved haplotypes with four distal flanking markers, suggesting the existence of at least two major mutations of Finnish origin. The genes MUT (methylmalonyl coenzyme A-mutase), RDS (retinal degeneration, slow), CSNK2 beta (casein kinase II, beta subunit), and GSTA1 (glutathione S-transferase alpha, type 1) were excluded as PKHD1 genes using both established and novel intragenic polymorphisms in families with key recombinants. These genetic data, combined with our YAC-based physical map of the 6p21-p12 region, will facilitate efforts to positionally clone the PKHD1 gene.

An integrated genetic and physical map of the autosomal recessive polycystic kidney disease region.

Autosomal recessive polycystic kidney disease is one of the most common hereditary renal cystic diseases in children. Genetic studies have recently assigned the only known locus for this disorder, PKHD1, to chromosome 6p21-p12. We have generated a YAC contig that spans approximately 5 cM of this region, defined by the markers D6S1253-D6S295, and have mapped 43 sequence-tagged sites (STS) within this interval. This set includes 20 novel STSs, which define 12 unique positions in the region, and three ESTs. A minimal set of two YACs spans the segment D6S465-D6S466, which contains PKHD1, and estimates of their sizes based on information in public databases suggest that the size of the critical region is < 3.1 Mb. Twenty-eight STSs map to this interval, giving an average STS density of < 1/150 kb. These resources will be useful for establishing a complete transcription map of the PKHD1 region.