| Human Molecular Genetics | Pages |
Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease (ADMCKD)
Introduction
Results
Establishment of linkage
Genetic mapping of the region and haplotype analysis
Identification of critical recombinants
Physical mapping by FISH
Discussion
Materials And Methods
Clinical material
Genotyping and DNA mapping
Linkage analysis
Haplotype analysis
Isolation of P1 clones and FISH mapping
Acknowledgements
Abbreviations
References
Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease (ADMCKD)
There is a group of inherited cystic nephropathies that are characterized by juvenile onset recessive inheritance (familial juvenile nephronophthisis, FJN) or by adult onset dominant inheritance (medullary cystic disease, MCD) and share similar clinico-pathological presentation to the extent that they are usually grouped together under the term FJN/MCD complex. The main symptoms consist of renal cyst formation in the medulla or the corticomedullary junction and salt wasting. Although earlier reports had suggested that one single gene may be responsible for this pathology, recent reports have shown that the FJN complex itself comprises a genetically heterogeneous group. Here we are presenting two large Cypriot families that segregate autosomal dominant medullary cystic kidney disease (ADMCKD) with hyperuricemia and gout and with very late age of onset (mean 62.2 and 51.5 years). We performed DNA linkage mapping using highly polymorphic microsatellite markers and found linkage to marker locus D1S1595 at 1q21 with a two-point lod score of 6.45 at [Theta] = 0.00. Analysis of haplotypes and of critical recombinants enabled confinement of the disease locus within an ~8 cM region between marker loci D1S498 and D1S2125. FISH mapping with a large P1 clone confirmed the physical localization within 1q21. The two families share the same disease haplotype, thus suggesting their relationship through a common ancestor and the possible existence of a single ADMCKD-causing mutation within these families. To our knowledge this is the first genetic locus identified to cause FJN/MCD pathology of the dominant adult type.
INTRODUCTION
Autosomal dominant medullary cystic kidney disease (ADMCKD) is an adult type inherited nephropathy characterized by formation of renal cysts, mainly at the corticomedullary junction, and by salt wasting. The disease was first recognized and described by Thorn et al. in 1944 (1) and shortly thereafter by Smith and Graham (2) and Fanconi (3), either as medullary cystic disease (MCD) or as familial juvenile nephronophthisis (FJN), due to the similar pathology of the two conditions. Subsequent reports suggested the similarity, if not identity, of these two conditions from the clinico-pathological perspective, although they follow a different mode of inheritance (4-9). On many occasions the term FJN/MCD complex is used for various conditions with similar clinical and pathological features. However, all authors tend to agree that MCD is a hereditary nephropathy with an autosomal dominant mode of inheritance affecting mainly adults (mean age 30-47 years depending on the series), whereas FJN is a similar disease entity with an autosomal recessive mode of inheritance and juvenile onset (10-12). Many patients are hypertensive at an early stage of the disease, but later some develop hypotension due to excessive salt wasting. Medullary cysts are present in most of the patients (75%), but unfortunately they cannot always be recognized on ultrasonography or a CT scan, since they are very small (13,14).
Nephronophthisis type 1 (NPH1, autosomal recessive medullary cystic kidney disease) was recently mapped and finely localized to chromosome 2q13 (15,16). In the majority of families and also of sporadic NPH cases the defect was large homozygous deletions spanning a region of 250 kb (16,17). Within this minimal region a gene, NPHP1, was recently identified. In the majority of cases it was indeed found to be homozygously deleted, but point mutations were also characterized (18). Genetic heterogeneity within the disease was evident from the existence of NPH families that are not linked to this disease locus (15,19). Senior-Loken syndrome, also referred to as NPH with extra-renal manifestations, has also been excluded from the chromosome 2q13 NPH1 locus (15). Allelism between the NPH1 locus and one large Cypriot family with ADMCKD associated with hyperuricemia and gout was excluded by us using the NPH1-linked marker locus D2S1888 (20). Also, the large homozygous deletions often found in patients with FJN type 1 were not detected in another small German ADMCKD family (21).
Table 1
| Locus | Family | Recombination fraction | [Theta]max | Zmax | ||||||
| 0.00 | 0.01 | 0.05 | 0.10 | 0.20 | 0.30 | 0.40 | ||||
| D1S1156 | 4901 | -inf | 1.45 | 2.46 | 2.58 | 2.18 | 1.47 | 0.62 | ||
| 4903 | 1.28 | 1.24 | 1.07 | 0.87 | 0.48 | 0.21 | 0.07 | |||
| Total | -inf | 2.68 | 3.53 | 3.45 | 2.66 | 1.68 | 0.68 | 0.063 | 3.55 | |
| D1S514 | 4901 | -inf | 1.42 | 2.45 | 2.59 | 2.18 | 1.42 | 0.52 | ||
| 4903 | 1.34 | 1.30 | 1.15 | 0.97 | 0.65 | 0.37 | 0.16 | |||
| Total | -inf | 2.72 | 3.60 | 3.56 | 2.83 | 1.79 | 0.68 | 0.068 | 3.64 | |
| D1S498 | 4901 | -inf | -0.18 | 0.96 | 1.24 | 1.16 | 0.77 | 0.28 | ||
| 4903 | 2.04 | 1.99 | 1.77 | 1.49 | 0.92 | 0.41 | 0.07 | |||
| Total | -inf | 1.81 | 2.73 | 2.73 | 2.08 | 1.18 | 0.35 | 0.072 | 2.78 | |
| D1S1153 | 4901 | 4.40 | 4.31 | 3.95 | 3.49 | 2.55 | 1.61 | 0.73 | ||
| 4903 | 1.98 | 1.94 | 1.76 | 1.53 | 1.06 | 0.60 | 0.20 | |||
| Total | 6.38 | 6.25 | 5.71 | 5.03 | 3.62 | 2.21 | 0.93 | 0.000 | 6.38 | |
| D1S1595 | 4901 | 4.54 | 4.45 | 4.09 | 3.62 | 2.67 | 1.71 | 0.78 | ||
| 4903 | 1.92 | 1.87 | 1.70 | 1.47 | 1.01 | 0.56 | 0.18 | |||
| Total | 6.45 | 6.32 | 5.78 | 5.09 | 3.68 | 2.26 | 0.96 | 0.000 | 6.45 | |
| D1S2125 | 4901 | 2.93 | 2.86 | 2.60 | 2.27 | 1.60 | 0.95 | 0.38 | ||
| 4903 | -inf | 0.37 | 0.89 | 0.97 | 0.81 | 0.53 | 0.23 | |||
| Total | -inf | 3.23 | 3.49 | 3.23 | 2.40 | 1.47 | 0.61 | 0.039 | 3.50 | |
| D1S1653 | 4901 | 2.68 | 2.62 | 2.38 | 2.08 | 1.48 | 0.91 | 0.39 | ||
| 4903 | 0.16 | 0.16 | 0.16 | 0.14 | 0.10 | 0.05 | 0.02 | |||
| Total | 2.84 | 2.78 | 2.54 | 2.22 | 1.58 | 0.96 | 0.41 | 0.000 | 2.84 | |
| D1S1679 | 4901 | -inf | 2.04 | 2.43 | 2.34 | 1.80 | 1.08 | 0.37 | ||
| 4903 | -inf | -1.52 | -0.89 | -0.62 | -0.30 | -0.13 | -0.04 | |||
| Total | -inf | 0.53 | 1.55 | 1.72 | 1.49 | 0.95 | 0.33 | 0.105 | 1.72 | |
| D1S1655 | 4901 | -inf | 1.46 | 1.92 | 1.91 | 1.54 | 1.00 | 0.42 | ||
| 4903 | -inf | -1.15 | -0.19 | 0.25 | 0.53 | 0.48 | 0.27 | |||
| Total | -inf | 0.31 | 1.72 | 2.16 | 2.07 | 1.48 | 0.69 | 0.134 | 2.22 | |
One major difficulty regarding ADMCKD is the absence of precise diagnostic criteria that could allow definitive differential diagnosis early on. Even histological examination of renal biopsies of affected individuals is not pathognomonic. The age of onset, especially in the two Cypriot families reported here, varies widely, ranging from 51 to 78 years in family CY4901 (mean 62.2) and from 39-65 years (mean 51.5) in family CY4903.
We performed linkage mapping of ADMCKD by a genome-wide linkage search using two large families. Linkage of ADMCKD to 1q21 was established with a maximum two-point lod score of 6.45 at [Theta] = 0.00 between the disease and marker locus D1S1595. Haplotype analysis enabled confinement of the disease region within an ~8 cM region between marker loci D1S498 and D1S2125. The two families share the same disease haplotype, thus suggesting their relationship through a common ancestor and the possible existence of a single ADMCKD-causing mutation within these families.
RESULTS
Establishment of linkage
Genome-wide screening was initiated with 45 individuals from one large Cypriot ADMCKD family (CY4901), 15 of whom are affected (20). Other at-risk individuals were assigned a liability class as described in Materials and Methods. Microsatellite polymorphic marker loci from screening set 6a (Research Genetics Inc.) at genetic distances of on average 24.2 cM were used. Two-point linkage analysis revealed a region of >80 cM on chromosome 1 that was not excluded. In addition, positive lod scores were obtained between the disease and marker loci D1S534, D1S1679 and D1S518 spanning this region. Four additional markers (D1S1675, D1S1595, D1S1677 and D1S1589) were analysed and the candidate region between D1S1679 and D1S534 was confirmed. Further investigation of the candidate region was performed with seven additional microsatellite marker loci: D1S1156, D1S514, D1S498, D1S1153, D1S2125, D1S1653 and D1S1655. At this point of the study a second large Cypriot ADMCKD family (CY4903) with 43 individuals, 10 of whom are affected, was included in the linkage analysis. A maximum cumulative two-point lod score of 6.45 at [Theta] = 0.00 was obtained between the disease and locus D1S1595. Two-point linkage analysis results are shown in Table 1.
Genetic mapping of the region and haplotype analysis
Ten CEPH-type families from our DNA bank were analysed in order to establish the genetic linkage map of the marker loci around the disease locus. The resulting map of the region is shown in Figure 1. . The following order of loci was obtained: cen-D1S1156-D1S514-D1S498-D1S1153-D1S1595-D1S2125- D1S1653-D1S1679-D1S1655-qtel. This linkage map was used to perform multipoint linkage analysis as described in Materials and Methods, mapping the disease locus against D1S498-(3.2)-D1S1153-(3.5)-D1S1595-(1)-D1S2125-(1.9)-D1S1653. A maximum multipoint lod score of 9.41 was obtained at locus D1S1595, thereby mapping the disease against the above fixed map of loci. Multipoint lod score results are shown in Figure 2. . Haplotypes of individuals were constructed following the above order of loci and the analysis results are in agreement with linkage of the disease to this region. The same affected haplotype was identified within the two families, thus providing evidence for the existence of a possible common ancestor.
Figure 1. Schematic diagram depicting part of chromosome 1 around the region of interest. Shown is the relative position of the markers used in this report for linkage analysis of the disease in the two families. The order of the markers was worked out after linkage analysis of 10 CEPH-like families from our DNA bank. The distances are in centiMorgans (cM). Figure 2. Multipoint linkage analysis results of the disease locus against the physical map of loci D1S498-(3.2 cM)-D1S1153-(3.5 cM)-D1S1595- (1 cM)-D1S2125-(1.9 cM)-D1S1653. The results are for both families together.
Identification of critical recombinants
A recombination event has been identified in an affected member, III-5, of family CY4903 between loci D1S1595 and D1S2125, locating the disease gene proximal to D1S2125 (Fig. 3). Also consistent with this finding is recombination between markers D1S2125 and D1S1653 in member III-7 of the same nuclear family. However, this is an asymptomatic at-risk individual who may or may not develop the disease in the future. Other critical recombinant haplotypes were identified in affected individuals from family CY4901, as past generation recombination events that had taken place between loci D1S498 and D1S1153, locating the disease gene distal to D1S498 (Table 2). These recombination events enabled placement of the disease region within an ~8 cM interval between loci D1S498 and D1S2125, in agreement with our multipoint linkage analysis results.
Figure 3. Part of pedigree CY4903. The predominant haplotype that is shared by most affected members in both families is shaded. The recombinant chromosome in individual III-5 suggests placement of the gene proximal to D1S2125. Table 2
Family
Individual
Disease haplotype
1156
514
498
1153
1595
2125
1653
1679
1655
4901
III 1
1
9
6
4
5
3
4
3
5
III 7
1
9
6
4
5
3
4
3
5
III 9
10
17
4
5
3
4
3
5
IV 1
1
9
6
4
5
3
4
3
5
IV 2
1
9
6
4
5
3
4
3
5
IV 5
1
9
6
4
5
3
4
-
5
IV 9
1
9
6
4
5
3
4
3
5
IV 13
1
9
6
4
5
3
4
3
5
IV 16
5
5
8
4
5
3
4
3
5
IV 17
5
5
8
4
5
3
4
2
6
IV 18
5
5
8
-
5
3
4
3
5
IV 20
5
5
8
4
5
3
4
3
5
IV 25
5
5
8
4
5
3
4
3
5
IV 28
5
5
8
4
5
3
4
3
5
IV 37
5
5
8
4
5
3
4
3
5
4903
III 5
5
5
8
4
5
4
3
4
1
III 9
5
5
8
4
5
3
4
3
5
III 11
5
5
8
4
5
3
4
3
5
III 13
5
5
8
4
5
3
4
3
5
IV 1
5
5
8
4
5
3
4
3
5
IV 4
5
5
8
4
5
3
4
3
5
IV 5
5
5
8
4
5
3
4
3
5
IV 6
5
5
8
4
5
3
4
3
5
IV 15
5
5
8
4
5
4
3
4
1
IV 23
5
5
8
4
5
3
4
3
5
Physical mapping by FISH
PCR screening of the CYPAC genomic library with polymorphic marker D1S1595, which provided the highest lod score, led to identification and isolation of five different clones. One of the clones, size ~115 kb, was used for FISH mapping on metaphase chromosomes. The unique localization of D1S1595 to chromosome 1q21 was accurately determined using DAPI banding and artificial G banding using Cytovision Ultra software (Applied Image) (Fig. 4).
Figure 4. Localization of a CYPAC clone isolated with marker D1S1595 to chromosome 1q21 by FISH of digoxigenin-labelled DOP-PCR products to metaphase chromosomes. Marker D1S1595 produced the highest lod score with each ADMCKD family separately.
DISCUSSION
We performed genome-wide genetic linkage analysis aimed at mapping an inherited interstitial nephropathy, ADMCKD, that is associated with hyperuricemia and gout, although with reduced penetrance. The patient material comprised two large Cypriot families originating from the Paphos district in the south-western part of Cyprus. The gene was mapped to chromosome 1q21 with a maximum two-point lod score of 6.45 at [Theta] = 0.00 at locus D1S1595. Strong linkage of ADMCKD to this region is supported by a maximum multipoint lod score of 9.41 at the D1S1595 locus, mapping the disease against the fixed map of D1S498- (3.2 cM)-D1S1153-(3.5cM)-D1S1595-(1 cM)-D1S2125-(1.9 cM)-D1S1653 loci. Haplotype analysis enabled restriction of the candidate region within an ~8 cM region between loci D1S498 and D1S2125, in agreement with the multipoint linkage analysis results. FISH mapping with a large P1 clone isolated with marker D1S1595 confirmed the genomic position of the relevant locus. A common disease haplotype was detected within these two families, suggesting the possibility of a single founder of the disease.
There are several different inherited kidney disorders that are characterized by formation of renal cysts. These are the dominant forms of polycystic kidney disease types 1, 2 and 3, the autosomal recessive form of polycystic kidney disease, nephronophthisis type 1 which maps to 2q13 and nephronophthisis unlinked to 2q13, Senior-Loken syndrome and ADMCKD. Although it is suggested that the PKD1 and PKD2 gene products may interact and participate in a common metabolic pathway, the putative relationships with other proteins will have to await isolation of additional involved genes and elucidation of their function and role in cyst formation. We have focused on ADMCKD with its clinical variants, which are characterized by the occasional association of such disparate non-renal manifestations as hyperuricemia and gouty arthritis, peripheral dysostosis, mental retardation, post-axial hexadactyly, cerebellar abnormalities, hypogonadism, obesity, renal tubular acidosis, parathyroid insufficiency and congenital amaurosis (for a review, see ref. 22). Also, earlier case reports presented an association of ADMCKD with gout and epilepsy (9) and spastic quadriparesis (23). Genetically it is presently unknown whether this clinical variability is due to allelic or locus heterogeneity or a combination of both. One hopes that investigations like the one presented here will assist in dissecting and classifying the genetics of these conditions.
The 8 cM interval within which the ADMCKD gene has been mapped is still very large and prohibitive for sequencing or screening of candidate genes. Therefore, many additional families need to be analysed in an effort to identify more useful critical recombinants that will assist in refining the disease region. It is important that both families described here share the same affected haplotype, although there are a few non-affected individuals who also share the same haplotype. These individuals may be double recombinants or falsely diagnosed, especially in view of the fact that the age of onset in both families is fairly advanced. It should be mentioned that these asymptomatic carriers of the younger generation, when examined by one of us (C.S.) in the absence of any molecular information, did not fulfil the criteria set out in Materials and Methods for them to be considered as affected by the disease. Therefore, they were initially assigned a 50% risk, except for two individuals, who were assigned a 75% risk as described in Materials and Methods. With the availability of closely linked flanking markers the liability of ultrasound or other imaging techniques can be investigated, by comparing the diagnosis after imaging and the diagnosis after DNA linkage analysis. This will eventually allow establishment of more reliable diagnostic criteria and liability classes based on age-dependent penetrance.
In view of the fact that the demand for prenatal diagnosis will most probably be minimal if not non-existent in this disease, its frequency is unlikely to decline in future generations. It is most imperative, therefore, to assist these patients with early presymptomatic diagnosis and try to prolong the normal function of their kidneys through close medical attention that may entail control of their hypertension and hyperuricemia and also a low protein diet. The linkage data and the markers available allow presymptomatic diagnosis to be performed as early as desired, especially in cases where relatives of patients are viewed as potential kidney transplant donors.
It is known that ADMCKD has a similar clinico-pathological presentation as juvenile onset nephronophthisis of recessive inheritance, although we and others have recently shown that there is no allelism between ADMCKD and NPH1, at least in the described families (20,21). It is reasonable to assume that the two diseases maybe the result of defects in the same developmental or metabolic pathway. The similarity in the phenotype may also be explained by similarities in the two genes mutated in each disease. Now that the gene for nephronophthisis type 1 (NPHP1) has been cloned and sequenced (18) it should not be difficult to search for a similarity with the locus identified here, once appropriate genomic clones have been isolated. The gene for nephronophthisis type 1, NPHP1, contains an SH3 domain, which is known to play a role in regulation of guanine nucleotide exchange factors of ras-like GTPases and is also involved in signal transduction pathways. In the large genomic interval on chromosome 1q21 between the flanking markers there are ~90 different transcripts found in transcript databases. Among these are calcium binding proteins, binding regulatory factors, proline-rich proteins, nuclear factors and growth factors and also genes highly similar to ras-related protein RAB-11A. However, most of the transcripts in that interval are of unidentified function or role and therefore remain candidates for the ADMCKD gene of our families.
The location on chromosome 1q21 is known to be syntenic to a region on murine chromosome 3. However, to our knowledge there is no gene mapping to that murine chromosome that is related to any cystic kidney disease. Nor are we aware of any other animal model for ADMCKD. The only related murine model, kdkd, was first described in 1971 (24). It referred to a recessive disease mapping to murine chromosome 10, having complete penetrance and being of autoimmune aetiology (25). Based on its clinico-pathological presentation it was considered to resemble human nephronophthisis, although this is known not to be an autoimmune disease.
Finally, our report further contributes to an understanding of the extent of the existing genetic heterogeneity among the various inherited cystic nephropathies. More importantly, it will allow advancement towards identifying the gene or genes involved and further clarification of the molecular defects.
MATERIALS AND METHODS
Clinical material
Two large families from the south-western part of Cyprus were included in this study. Based on detailed clinical, biochemical and pathological evaluation of patients the diagnosis of ADMCKD was proposed (20). Linkage to NPH1, mutations in which cause the most frequent form of nephronophthisis, was tested and excluded for family CY4901 (lod score -2.03; ref 20). Both families extend to five generations and DNA was available from 88 individuals (45 of family CY4901 and 43 of family CY4903), 25 of whom are affected (15 and 10 respectively). Seventeen of these patients were male and eight were female. Interestingly, both families had a history of gout or hyperuricemia associated with the medullary cystic disease, although with reduced penetrance (20).
Genotyping and DNA mapping
Approximately 20 ml EDTA-anticoagulated blood was collected from affected and non-affected members of the families investigated. DNA extraction was performed by the salting-out method of Miller et al. (26). Initially 45 individuals from family CY4901 were analysed with microsatellite polymorphic marker loci from screening set 6a (Research Genetics Inc.) at distances of on average 24.2 cM. PCR amplification and analysis were performed as described previously (27). After linkage was established for family CY4901 43 members of the second family, CY4903, were also examined with the relevant markers.
Linkage analysis
Two-point and multipoint analyses were performed using the LINKAGE package of programs (28). Allele frequencies were estimated using the individuals married into the families. Equal male and female recombination fractions were assumed and a disease gene frequency of 10-4 was used. Two liability classes were used for at-risk individuals based on the clinico-pathological profile, with 50 and 75% risk of being affected. Subjects were considered as affected if they had a biopsy proven chronic interstitial nephritis compatible with medullary cystic disease or if they had decreased corrected creatinine clearance (<80 ml/min) or if they had more than two bilateral medullary cysts. A risk of 75% was given to individuals who had two or more of the following criteria: solitary renal cysts, decreased fractional excretion of uric acid, history of gout, hyperuricemia or hypertension. At-risk members who did not fulfil the above criteria were given a 50% risk.
Haplotype analysis
Haplotypes of individuals were constructed following the order in which the loci were mapped using the 10 CEPH-type families from our DNA bank: cen-D1S1156-D1S514-D1S498-D1S1153- D1S1595-D1S2125-D1S1653-D1S1679-D1S1655-qtel. Recombination events were detected and used to flank the candidate region on both sides.
Isolation of P1 clones and FISH mapping
Polymorphic marker D1S1595 was used for PCR screening of a P1-like human genomic library (29). One of the CYPAC clones isolated, size ~115 kb, was used for FISH mapping as previously described, with digoxigenin-labelled DOP-PCR products to metaphase chromosomes (30). The cloned DNA was used as template for PCR amplification with the degenerate primer 6-MW (5[prime]-CCG ACT CGA GNN NNN NAT GTG G-3[prime]) in three stages as described by Kroisel et al. (31). During the third stage PCR the nucleotide analogue digoxigenin-11-dUTP was used for internal labelling of the products. The slides were viewed under a Zeiss Axioskop fluorescence microscope and the images were analysed with Cytovision (Applied Image) software. The photographs were taken with a CCD monochrome camera.
ACKNOWLEDGEMENTS
We would like to thank Anthi Georghiou for kind technical assistance. This work was partly funded by the Cyprus Ministry of Health and by a grant from the Cyprus Kidney Association (CCD).
ABBREVIATIONS
ADMCKD, autosomal dominant medullary cystic kidney disease; FISH, fluorescent in situ hybridization; FJN, familial juvenile nephronophthisis; MCD, medullary cystic disease.
REFERENCES
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 I Takayama, Y Daigo, S M Ward, K M Sanders, R L Walker, B Horowitz, T Yamanaka, and M A Fujino Novel human and mouse genes encoding an acid phosphatase family member and its downregulation in W/WV mouse jejunum Gut, June 1, 2002; 50(6): 790 - 796. [Abstract] [Full Text] [PDF]
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N. Basora, H. Nomura, U. V. Berger, C. Stayner, L. Guo, X. Shen, and J. Zhou Tissue and Cellular Localization of a Novel Polycystic Kidney Disease-Like Gene Product, Polycystin-L J. Am. Soc. Nephrol., February 1, 2002; 13(2): 293 - 301. [Abstract] [Full Text] [PDF]
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T. Apostolou, N. Nikolopoulou, M. Theodoridis, V. Koumoustiotis, E. Pavlopoulou, D. Chondros, and A. Billis Late onset of renal disease in nephronophthisis with features of Joubert syndrome type B Nephrol. Dial. Transplant., December 1, 2001; 16(12): 2412 - 2415. [Full Text] [PDF]
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K. DAHAN, A. FUCHSHUBER, S. ADAMIS, M. SMAERS, S. KROISS, G. LOUTE, J.-P. COSYNS, F. HILDEBRANDT, C. VERELLEN-DUMOULIN, and Y. PIRSON Familial Juvenile Hyperuricemic Nephropathy and Autosomal Dominant Medullary Cystic Kidney Disease Type 2: Two Facets of the Same Disease? J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2348 - 2357. [Abstract] [Full Text] [PDF]
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F. HILDEBRANDT and E. OTTO Molecular Genetics of Nephronophthisis and Medullary Cystic Kidney Disease J. Am. Soc. Nephrol., September 1, 2000; 11(9): 1753 - 1761. [Abstract] [Full Text]
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S. Kroiss, K. Huck, S. Berthold, F. Ruschendorf, F. Scolari, G. Caridi, G. M. Ghiggeri, F. Hildebrandt, and A. Fuchshuber Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease Nephrol. Dial. Transplant., June 1, 2000; 15(6): 818 - 821. [Abstract] [Full Text] [PDF]
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E. OTTO, A. KISPERT, S. SCHATZLE, B. LESCHER, C. RENSING, and F. HILDEBRANDT Nephrocystin: Gene Expression and Sequence Conservation between Human,Mouse, and Caenorhabditis Elegans J. Am. Soc. Nephrol., February 1, 2000; 11(2): 270 - 282. [Abstract] [Full Text] [PDF]
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 Z. Liu, J. Peng, R. Mo, C.-c. Hui, and C.-H. Huang Rh Type B Glycoprotein Is a New Member of the Rh Superfamily and a Putative Ammonia Transporter in Mammals J. Biol. Chem., January 5, 2001; 276(2): 1424 - 1433. [Abstract] [Full Text] [PDF]
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