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*
Center for Human Genetics, Catholic University of Louvain, Brussels,
Belgium
Department of Pathology, Catholic University of Louvain, Brussels,
Belgium
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Division of Nephrology, Catholic University of Louvain, Brussels,
Belgium
University Children's Hospital, Freiburg, Germany
Department of Nephrology, Princesse Paola Hospital, Aye,
Belgium.
Correspondence to Dr. Karin Dahan, Center for Human Genetics, Université Catholique de Louvain, Avenue E, Mounier 52, Tour Vésale 5220, B-1200 Brussels, Belgium. Phone: 0032-2-764-52-20; Fax: 0032-2-764-52-22; E-mail: Dahan{at}gmed.ucl.ac.be
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Abstract |
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= 0), was observed in
this study. The candidate region was further narrowed to a 1.3-Mb interval
between D16S501 and D16S3036. Together with the striking clinical and
pathologic resemblance between previously reported medullary cystic kidney
disease type 2 and FJHN occurring in the Belgian family (including the
presence of medullary cysts), this study suggests that these two disorders are
facets of the same disease. |
Introduction |
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The nature of the molecular defect accounting for FJHN is unknown. The
search for candidate genes may be guided by either the biochemical or
histologic characteristics of the condition. The hypoexcretion of uric acid
indicates a defect involving the tubular transport of uric acid in the
proximal tubular epithelium. A candidate gene could be UAT, a gene
for a specific urate transporter that was isolated from a rat renal cDNA
library (11,
12). UAT protein functions as
a selective, voltage-sensitive, urate transporter channel; it has been
observed to be localized within the brush border membrane of proximal tubules
(11). The deduced amino acid
sequence of the cDNA predicts a transmembrane protein with a carboxy-terminal
domain highly homologous (
98%) to the ß-galactoside-binding lectin
domain of galectin 5 (LGALS5), which was isolated from rat
erythrocytes (13). The
LGALS5 gene has been mapped to mouse chromosome 11, approximately 50
cM from the centromere, in a region syntenic with human chromosome 17q11
(13).
Alternatively, hyperuricemia could be the first manifestation of a tubular defect that concurrently leads to interstitial fibrosis and progressive renal failure. The marked thickening of tubular basement membranes observed in FJHN is similar to that observed in the nephronophthisis (NPH)-autosomal medullary cystic kidney disease (MCKD) group of diseases. Juvenile NPH (NPH1, MIM 256100) and adolescent NPH (NPH2, MIM 602088) are autosomal recessive diseases that lead to ESRF in adolescence, whereas autosomal dominant MCKD (MCKD1, MIM 174000; MCKD2, MIM 603860) leads to ESRF during adulthood. Remarkably, a history of gout and/or hyperuricemia was also noted for several members from four of 12 kindreds with MCKD reported in the literature (14,15,16,17). Histologic and clinical similarities between FJHN and MCKD thus suggest the possibility of a connection between the two entities. Recent advances in the molecular genetic understanding of MCKD could shed light on its relationship with FJHN. Two different loci for MCKD have been mapped, MCKD1 on chromosome 1q21 in two Cypriot families (18) and MCKD2 on chromosome 16p12 in an Italian family (19). Very recently, FJHN was mapped, in a large Japanese family (20) and in two Czech families (21), to chromosome 16p11 at a location very close to MCKD2, raising the question of whether distinct genes for MCKD2 and FJHN are colocalized within the approximately 10-cM region delimited by the authors or whether these two disorders represent two phenotypic forms of a defect in the same gene (20, 21).
We report on a large Belgian family with FJHN, including 14 affected members. All affected members met strict criteria for FJHN, and medullary cysts were present in all three available nephrectomy specimens. We performed positional linkage analysis of the specific urate transporter UAT/LGALS5 and the MCKD1 and MCKD2 loci. We observed a significant linkage to the marker D16S3060, located at the MCKD2/FJHN loci. Furthermore, we narrowed the candidate region for the FJHN locus to a 1.3-Mb interval between D16S501 and D16S3036. Together with the striking clinical and pathologic resemblance between previously reported MCKD2 and FJHN in our family (including the presence of medullary cysts), this study suggests that these two disorders are two facets of the same disease.
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Materials and Methods |
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We defined as affected either patients with ESRF and a history of gout
(subjects II-1, III-1, III-5, IV-3, IV-5, IV-13, and IV-14) or patients with
serum creatinine concentrations of 
1. 4 mg/dl and serum uric acid
concentrations >1 SD greater than the normal values for age and gender
(<5 yr, 3.6 ± 0.9 mg/dl; 5 to 10 yr, 4.1 ± 1 mg/dl; male, 12
yr, 4.4 ± 1.1 mg/dl; male, 15 yr, 5.6 ± 1.1 mg/dl; male, 18
yr, 6.2 ± 0.8 mg/dl; female, 12 yr, 4.5 ± 0.9 mg/dl; female, 15
yr, 4.5 ± 0.9 mg/dl; female, 18 yr, 4 ± 0.7 mg/dl)
(22) (subjects IV-1, IV-8,
IV-10, V-2, V-3, and V-9).
Fourteen subjects were found to be affected. The clinical characteristics
of the 12 investigated subjects are presented in
Table 1. Subject II-1, who died
at 75 yr of age, had a history of gout and renal failure. No information was
obtained for subject II-3, who is an obligate carrier. Among subjects
belonging to generations III and IV, six (subjects III-1, III-5, IV-3, IV-5,
IV-13, and IV-14) experienced ESRF at ages ranging from 28 to 63 yr, with a
history of gout preceding ESRF by 4 to 35 yr. Kidney ultrasonography
(performed at the stage of renal failure) revealed no cyst for four
individuals, one cyst for two individuals, and two cysts for one individual.
Among other at-risk subjects belonging to generations IV and V, none had a
history of gout and all exhibited serum creatinine concentrations of 1.4
mg/dl. On the basis of serum uric acid concentrations, six of those subjects
(subjects IV-1, IV-8, IV-10, V-2, V-3, and V-9) were considered to be affected
and five (subjects IV-11, V-4, V-6, V-7, and V-8) were considered to be
normal. The status of two subjects (subjects V-1 and V-5) who were not
investigated was considered to be undetermined.
Genotyping
Genomic DNA was available for 12 affected individuals, nine unaffected
individuals, and two individuals of undetermined status. DNA was extracted
from leukocytes by using standard techniques. We performed linkage analysis
with eight microsatellites spanning approximately10 to 20 cM (D17S122,
D17S805, D17S783, D17S1800, D17S1880, D17S798, D17S933, and D17S800) of the
chromosomal region 17q11 (a candidate for LGALS5). The sequence
information and the genomic order of microsatellite markers used for linkage
analysis of chromosome 17q11 were obtained from the
Généthon
gender-averaged genetic map
(23) and the Genome
Database.
Three polymorphic microsatellite markers from 1q21 (D1S1153, D1S1593, and D1S2125) and three markers from 16p12 (D16S3017, D16S3036, and D16S3041) were selected, on the basis of their demonstrated high logarithmic odds (LOD) scores in the identification of MCKD1 and MCKD2 loci, respectively. Their order was initially based on the works of Christodoulou et al. (18) and Scolari et al. (19). Subsequently, when evidence of linkage was obtained for the 16p12 locus, additional polymorphic markers selected from the available databases (D16S3114, D16S3069, D16S764, D16S3060, D16S287, D16S3103, and D16S499) were analyzed, to determine whether analysis of recombinant individuals within this family would permit refinement of the published FJHN interval (20, 21). Fluorescence markers were custom-synthesized by Genset (Paris, France). Expected size information and allele frequencies were obtained from either the Genome Database or the Whitehead Institute for Biomedical Research/MIT Center for Genome Research.
In brief, markers were amplified by using a fluorescently labeled primer
and AmpliTaq polymerase (Perkin-Elmer, Norwalk, CT), in a 20-µl reaction
volume containing 50 ng of genomic DNA, 10 pmol of each primer, 1 mM dNTP, and
standard reaction buffer. The resultant PCR products were electrophoresed
through a 4% denaturing polyacrylamide gel in an ABI 373 automated DNA
sequencer (Applied Biosystems, Foster City, CA). Gel data were extracted by
using ABI Genescan software, and the microsatellite peaks were sized with the
same program. For seven of the 10 chromosome 16p markers, the PCR products
were radiolabeled by incorporation of [
-32P]dCTP (Amersham,
Arlington Heights, IL). PCR-derived products were loaded, in groups of two or
three (according to the expected sizes of the DNA fragments), on a sequencing
polyacrylamide gel containing 6 M urea, 37.5% formamide, and
Tris-borate-ethylenediaminetetraacetate buffer. Gels were developed at 100 W
for 3 h (4°C), dried, and exposed to Kodak x-ray film (Eastman Kodak,
Rochester, NY) for 1 to 12 h at room temperature.
Linkage Analysis
The alleles were assigned to individuals, which allowed calculation of
two-point LOD scores with Cyrillic version 2.0 (Cherwell Scientific) and MLINK
(24) software programs. For
the two-point LOD scores and the multipoint linkage analyses, FJHN was modeled
as an autosomal dominant trait with a disease ailele frequency of 0.0001. Full
penetrance was assumed for affected individuals. The marker allele frequencies
were uniformly distributed. Calculations using marker allele frequencies
reported in available databases were also performed, but these changes had
minimal effects on the LOD scores generated. The number of alleles was
estimated on the basis of either information from the Genome Database, if
available, or the number of alleles observed in the study samples. Alleles
were scored, and genotype data were entered into the pedigree file of the
linkage package. Therefore, at any given locus, results for the 14 affected
individuals were used to generate a final LOD score for each marker tested. In
addition, multipoint analyses were performed by using a parametric multipoint
linkage program included in the Gene Hunter program
(25). Mapping information was
obtained from the United Database (UDB)
(http://bioinformatics.weizmann.ac.il), which is based on combined genetic,
radiation hybrid, and physical mapping findings (contig content) and contains
very recent data. The marker order, according to the UDB, is as follows (with
relative map positions in parentheses): ptel-D16S3114 (25.756 Mb)-D16S3069
(29.196 Mb)-D16S764 (33.204 Mb)-D16S3060 (33.560 Mb)-D16S287 (34.408
Mb)-D16S3017 (35.248 Mb)-D16S3103 (35.248 Mb)-D16S499 (35.521 Mb)-D16S3036
(36.472 Mb)-D16S3041 (36.993 Mb)-cen.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Linkage Analysis
We initially genotyped all individuals with eight polymorphic
microsatellite repeats (D17S122, D17S805, D17S783, D17S1800, D17S1880,
D17S798, D17S933, and D17S800) spanning approximately 10 to 20 cM of the
chromosomal region 17q11, which is syntenic with the LGALS5 mouse
locus. Two-point analysis was performed, and results were consistent with an
exclusion. Indeed, this region was excluded on the basis of recombination and
LOD scores well below -2 (data not shown).
Linkage analysis of the three markers of MCKD1 located within the
approximately 8-cM critical interval between D1S498 and D1S2125 demonstrated
no cosegregation between the 12 affected individuals and the haplotype
associated with the disease, demonstrating that FJHN is not allelic with
MCKD1 in this family (data not shown). Linkage analysis of the three
markers of MCKD2 demonstrated significant linkage for marker
D16S3017, with a maximal LOD score of 3.2 at a recombination fraction
(max) of 0, whereas linkage to the markers D16S3041 and
D16S3036 was excluded. A two-point analysis was then performed between the
putative FJHN locus and four additional polymorphic markers
(D16S3060, D16S287, D16S3103, and D16S499) located within the approximately
10.5-cM critical region previously described by Scolari et al.
(19) as the MCKD2
locus, as well as three telomeric markers (D16S3114, D16S3069, and D16S764).
Two markers flanking the D16S3017 marker (D16S3060 and D16S3103) demonstrated
significant LOD scores of >3, with no recombination. The maximal two-point
LOD score of 3.74 was obtained with the marker D16S3060, at a maximal
recombination fraction (max) of 0
(Table 2).
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We then performed a parametric multipoint linkage analysis with the Gene Hunter version 2.0 beta (r2) program under the autosomal dominant model, as described in the Materials and Methods section. The order of loci obtained from the integrated UDB map (entry, March 19, 2001) (Figure 3A4) was as follows: ptel-D16S3114 (25.7 Mb)-D16S3069 (29.2 Mb)-D16S764 (33.2 Mb)-D16S3060 (33.6 Mb)-D16S287 (34.4 Mb)-D16S3017 (35.2 Mb)-D16S3103 (35.2 Mb)-D16S499 (35.5 Mb)-D16S3036 (36.5 Mb) and D16S3041 (37 Mb)-cen. For the program, distances between two markers are assumed on the basis of 1 cM representing 106 bases. The multipoint LOD scores were not different from the two-point LOD scores, with a maximal multipoint LOD score of 3.7 at markers D16S3017 and D16S3103. Multipoint LOD score results are presented in Figure 4.
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Haplotype Studies
To refine the FJHN locus, we constructed detailed haplotypes using
the same 16p markers that were used for the linkage analyses. The pedigree
with haplotypes was drawn using the Cyrillic program and is presented in
Figure 1. A common haplotype,
i.e., 2-1-1-4-2 for markers D16S764, D16S3060, D16S287, D16S3017, and
D16S3103, is shared by all affected individuals, including subjects IV-1,
IV-8, IV-10, V-2, and V-9, who exhibit only hyperuricemia resulting from low
fractional excretion of uric acid (Table
1). This is in accord with the data in
Table 2 that indicated that the
LOD scores for the markers D16S3060, D16S3017, and D16S3103 were >3 at
= 0 when the penetrance was set at 1. In contrast, subject V-4, who is
clearly unaffected (Table 1),
has received the grandpaternal normal haplotype.
Haplotype analysis revealed two recombinant events, narrowing the critical interval for FJHN. As shown in Figure 1, the recombination observed with marker 16S3036 in an affected member (subject IV-8) helps to define the centromeric boundary to marker D16S3036, whereas the recombination event observed for marker D16S3069 in five affected members (subjects III-5, IV-5, IV-13, IV-14, and V-9) defines the telomeric boundary to marker D16S3069. In subjects IV-8 and V-8, the distal marker (D16S499) is homozygous and uninformative; therefore, the possibility of recombination events between markers D16S3103, D16S499, and D16S3036 remains undetermined. The recombination breakpoints were therefore located distal to marker D16S3069 at 29.2 Mb and proximal to marker D16S3036 at 36.5 Mb from the telomere (Figure 3, A4 and B4).
Refinement of the FJHN Locus
The mapping data, with critical recombinations observed in the Japanese and
Czech families
(20,21)
and in this family, are depicted in Figure
3. This diagram, which allows cross-reference with the available
mapping databases, was determined by alignment of genetic and physical maps of
the FJHN critical regions for the Japanese
(20), Czech
(21), and Belgian families.
Linkage analysis results reported for our family confirm the localization of
the FJHN locus in the p12 region of chromosome 16
(20,21).
The relative location of the critical region observed in the single large
Japanese family (20) is
controversial. Indeed, using a genetic map such as the Marshfield map, the
critical region lies between markers D16S403 (at 42.7 cM) and D16S3116 (at
50.6 cM) (Figure 3A3), with a
dominant haplotype, shared by all affected individuals, for the five following
markers: ptel-D16S417-D16S420-D16S3113-D16S401-D16S3133-cen. However, using an
integrated database such as the UDB map, which is derived from various mapping
and recent sequencing resources for the human genome
(26,27),
the order of the nine markers used in this study
(Figure 3A4) is now (entry of
March 19, 2001) as follows: ptel-D16S3133 (37.3 Mb)-D16S3113 (37.3 Mb)-D16S403
(39.4 Mb)-D16S3116 (39.6 Mb)-D16S412 (40.1 Mb)-D16S417 (41.6 Mb)-D16S420 (42.1
Mb)-D16S401 (42.5 Mb) and D16S3093 (42.6 Mb). The recombination events
observed by Kamatani et al.
(20) for markers D16S403 and
D16S3116 (at 39.4 and 39.6 Mb, respectively) probably help define a
centromeric boundary, whereas the absence of recombination events for the
telomeric markers D16S3113 and D16S3133 (at 37.3 Mb) is consistent with a
linkage to the disease at this locus, with a maximal LOD score of 5.13 for
D16S3113 at a recombination fraction (max) of 0
(Figure 3B3). In contrast, the
FJHN critical region defined in this study
(Figure 3B4) shows overlap with
that reported for two Czech families
(Figure 3B2). The FJHN
critical interval is flanked by two recombination events, at markers D16S501
(35.2 Mb) and D16S3036 (36.5 Mb) in the Czech and Belgian families,
respectively. These two informative recombinations can be used to exclude
either centromeric or telomeric portions of 16p12 from carrying the mutated
gene. Because the telomeric border for the FJHN locus was previously
defined as D16S501 (20) and
because, in this study, the centromeric border was delimited to D16S3036, the
FJHN locus is now refined to the interval
tel-D16S501-FJHN-D16S3036-cen, which measures approximately 4.8 cM on
the Marshfield genetic map (Figure
3A2) or 1.3 Mb on the UDB map
(Figure 3A4). This 4.8-cM
interval is located within the MCKD2 critical interval, which was
identified by Scolari et al.
(19) as being between D16S500
and SCNN1B1—2 (Figure
3A1).
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Discussion |
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max) of 0 for one marker (D16S3060) located within the
approximately 10.5-cM critical region previously described by Scolari et
al. (19) as the
MCKD2 locus. Strong linkage of FJHN to the MCKD2 locus is
supported by LOD scores of >3, with no recombination, for two other markers
(D16S3017 and D16S3103) flanking the D16S3060 marker. This location on
chromosome 16p confirms the findings from the recent studies by Stiburkova
et al. (21) and
Kamatani et al. (20),
who demonstrated, in two Czech families and a single large Japanese family
with FJHN, respectively, strong linkage to the same chromosomal interval
(Figure 3). However, with the
use of a genetic map such as the Marshfield map, the critical region between
markers D16S403 and D16S3116 reported by Kamatani et al.
(20) demonstrates no overlap
with the critical region between markers D16S3069 and D16S3036 defined for the
Belgian family. This finding could be accounted for by the existence of two
homologous genes lying in close proximity. Alternatively, genotyping errors or
inconsistencies in the genetic maps could lead to misinterpretations in the
definition of critical intervals. Interestingly, by using markers located on
chromosome 16p12 between D16S403 and D16S3116, nonoverlapping critical regions
have been identified in different families affected by benign familial
infantile convulsions (28).
This finding raises questions regarding the positions of the markers defining
the critical interval in the Japanese family
(20). The order of these
markers has indeed been recently modified by using more accurate sequencing
data resources (Figure 3A4)
(26,27),
leading to a novel interpretation of the critical region. Using genotype data
and two-point LOD scores provided by Kamatani et al.
(20), it is impossible to
redefine a critical interval flanked by two crossover events with the disease
locus, which should represent the outer boundaries of the linked region on
chromosome 16p12. Therefore, only haplotype analyses performed for the Czech
and Belgian families allow restriction of the candidate region for
FJHN within a 4.8-cM region between loci D16S501 and D16S3036, in
agreement with the intermarker distances according to the Marshfield genetic
map (Figure 3A2) or the UDB map
(Figure 3A4). Most
interestingly, this interval is located within the MCKD2 critical
interval, which was identified by Scolari et al.
(19) as being between D16S500
and SCNN1B1—2 (Figure
3A1). The next question is whether the genes for FJHN and MCKD2 are close to each other or the two disorders are actually a single entity (21). A detailed review of the data for families reportedly affected by MCKD, as well as our own findings, strongly argue for the existence of very close, perhaps similar, entities. Among 12 families with MCKD described in the literature (14,15,16,17,29,30), a history of gout and hyperuricemia was mentioned for several subjects from four families (Table 3). Furthermore, low fractional excretion of uric acid was observed for two at-risk teenage subjects affected by MCKD (14), as well as young at-risk subjects from families with FJHN (31). The clinical presentation of the family reported by Scolari et al. (17), in which the MCKD2 locus was mapped (19), shares many similarities with the presentation of our family, i.e., hyperuricemia was observed for five of seven patients, the age of ESRF ranged from 33 to 63 yr, and chronic interstitial nephritis, with marked thickening of tubular basement membranes, was observed for four of four patients. Of note, cysts were detected during imaging for only a minority of patients with MCKD, including only one of the seven patients reported by Scolari et al. (17,19). Only at autopsy, which was performed for a few patients, was the presence of medullary cysts indisputable (14,15).
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In our family (which meets all criteria for FJHN), we demonstrate, for the first time for this disease, the existence of medullary cysts characteristic of so-called MCKD. Interestingly, these cysts seem to be a late phenomenon and can easily escape imaging detection. In this family, ultrasonography indeed failed to detect any cysts for four adults with chronic renal failure (age range, 34 to 54 yr), as well as two affected children (ages, 5 and 14 yr). For one adult, ultrasonographic results were negative at 34 yr of age but demonstrated one cyst in each kidney 5 yr later. For another adult, ultrasonography demonstrated two cysts in each kidney but computed tomography demonstrated multiple bilateral cysts 3 yr later. The ultimate proof of the existence of medullary cysts in this family was provided only by the nephrectomy specimens; in each of three cases, several medullary cysts were clearly present. The poor results of conventional imaging in the detection of medullary cysts could explain why this finding was hitherto unreported for FJHN.
Our finding of the hallmarks of both FJHN and MCKD in our family supports the hypothesis of allelism, which is consistent with DNA linkage analysis results. It can be imagined that the same disease was termed FJHN by some authors when the first manifestation was early gout, especially when it occurred among young nonobese subjects, and was termed MCKD by other investigators when cysts were detected in shrunken kidneys, especially when hyperuricemia was lacking. FJHN and MCKD could thus be allelic variants. In other families with FJHN, it would be of interest to carefully search for the existence of medullary cysts and to test for linkage to both MCKD1 and MCKD2 loci. Conversely, fractional excretion of uric acid should be measured for affected and at-risk subjects from families with MCKD.
A search for candidate genes localized within the approximately 4.8-cM
region on the Marshfield genetic map
(Figure 3A2) or the 1.3-Mb
region on the UDB map identified a large number of expressed-sequence tags
mapped by radiation hybrid analysis to the D16S501 to D16S3036 interval,
together with four complete cDNA (GeneMap 1999 and UDB). Among the genes noted
in the critical region, we observed two complete sequences for cDNA of unknown
human genes, termed KIAA0421 and KIAA0419, which were
isolated from different sources, including human kidney cDNA libraries.
Because these two predicted amino acid sequences have not yet been classified
in a functional category, their potential effects remain unknown. A third
transcript is a potential central metabolic regulator belonging to the
coenzyme Q7 family, members of which are known to regulate ubiquinone
biosynthesis and function as an electron transport component and a
lipid-soluble antioxidant
(32). The COQ7 gene
is well conserved among mammal, bird, and reptile genomes and is dominantly
transcribed in heart and skeletal muscle, likely localized in the
mitochondrial inner membrane
(33). Therefore, the
COQ7 gene does not seem to be a candidate gene for FJHN. The fourth
cDNA located within the defined critical region is involved in G
protein-coupled signaling. Named GPRC5B (G protein-coupled receptor family C,
group 5, member B), it contains a signal peptide and seven transmembrane
-helices, which are hallmarks of G protein-coupled receptors
(34). G protein-coupled
receptors constitute a large class of proteins that are divided into three
families (family A, rhodopsin receptor-like; family B, secretin receptor-like;
family C, metabotropic glutamate receptor-like) and are thought to transmit a
variety of signals from the extracellular milieu to the intracellular milieu
(35). GPRC5B displays homology
to retinoic acid-inducible gene 1 (RAIG1) protein. Both RAIG1 and GPRC5B have
short extracellular amino-terminal domains, which is strikingly different from
the majority of family C receptors characterized by large amino-terminal
domains. The two related transcripts, GPRC5B and RAIG1, are distinctly
expressed, with the highest mRNA levels for RAIG1 in lung tissue and the
highest levels for GPRC5B in kidney
(34). On the basis of their
transcriptional induction by retinoic acid, it has been speculated that these
transcripts could be involved in modulation of differentiation and maintenance
of homeostasis of epithelials cells or in embryonic development and maturation
of fetal lung and kidney (36).
Interestingly, FJHN and MCKD are diseases characterized by severe changes in
the renal interstitium, with accumulation of collagen fibers and disruption of
tubular basement membranes. Because these changes could be mediated by G
protein-coupled receptors
(37), the GPRC5B gene
is a potential candidate for mutation analysis.
However, the 4.8-cM interval containing the FJHN gene, which spans 1.3 Mb on the integrated map, is still large for sequencing and mutation screening of candidate genes. Analyses of additional families and other genetic markers should help to further restrict the critical interval and establish the possible allelism between MCKD2 and FJHN. The ultimate proof of the latter hypothesis can be provided only by identification of the responsible gene. Elucidation of the molecular bases of MCKD and FJHN should help clarify the classification of hereditary interstitial nephritides and cystic diseases. It should also cast some light on the mechanism of urate hypoexcretion and, it is hoped, expand therapeutic possibilities.
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K. Dahan, O. Devuyst, M. Smaers, D. Vertommen, G. Loute, J.-M. Poux, B. Viron, C. Jacquot, M.-F. Gagnadoux, D. Chauveau, et al. A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2883 - 2893. [Abstract] [Full Text] [PDF]
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 T C Hart, M C Gorry, P S Hart, A S Woodard, Z Shihabi, J Sandhu, B Shirts, L Xu, H Zhu, M M Barmada, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy J. Med. Genet., December 1, 2002; 39(12): 882 - 892. [Abstract] [Full Text] [PDF]
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 L.D. FAIRBANKS, J.S. CAMERON, G. VENKAT-RAMAN, S.P.A. RIGDEN, L. REES, W. VAN'T HOFF, M. MANSELL, J. PATTISON, D.J.A. GOLDSMITH, and H.A. SIMMONDS Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease QJM, September 1, 2002; 95(9): 597 - 607. [Abstract] [Full Text] [PDF]
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P. Kotanko, E. Gebetsroither, and F. Skrabal Familial juvenile hyperuricaemic nephropathy in a Caucasian family associated with inborn malformations Nephrol. Dial. Transplant., July 1, 2002; 17(7): 1333 - 1335. [Full Text] [PDF]
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