Abstract. In a large Venezuelan kindred, a new type of
nephronophthisiswas recently identified: Adolescent nephronophthisis (NPH3)
isa late-onset recessive renal cystic disorder of the
nephronophthisis/medullarycystic group of diseases causing end-stage renal
disease ata median age of 19 yr. With the use of a homozygosity mapping
strategy,the gene (NPHP3) was previously localized to chromosome
3q22within a critical interval of 2.4 cM. In the current study,the
NPHP3 genetic region was cloned and seven genes, eight expressed
sequence-taggedsites, and seven microsatellites were physically localized
withinthe critical disease interval. By human-mouse synteny analysisbased on
expressed genes, synteny between the human NPHP3 locuson chromosome
3q and the pcy locus on mouse chromosome 9 wasclearly demonstrated,
thus providing the first evidence of syntenybetween a human and a spontaneous
murine renal cystic disease.By fluorescence in situ hybridization
the chromosomal assignmentof NPHP3 to chromosome 3q21-q22 was
refined. Renal pathologyin NPH3 was found to consist of tubular basement
membranes changes,tubular atrophy and dilation, and sclerosing
tubulointerstitialnephropathy. This pathology clearly resembled findings
observedin the recessive pcy mouse model of late-onset polycystic
kidneydisease. In analogy to pcy, renal cyst development at the
corticomedullaryjunction was found to be an early sign of the disease.
Throughcloning of the NPH3 critical region and mapping of expressedgenes,
synteny between human NPH3 and murine pcy was established,thus
generating the hypothesis that both diseases are causedby recessive mutations
of homologous genes.
Nephronophthisis (NPH), an autosomal-recessive cystic kidneydisorder, is a
major genetic cause of chronic renal diseasein children
(1). Recently, we identified
adolescent nephronophthisis(NPH3) as a novel type of NPH in a large
consanguineous Venezuelankindred. Applying a homozygosity mapping strategy,
we localizedthe responsible gene (NPHP3) to a critical interval of
2.4 cMon chromosome 3q (2).
Juvenile nephronophthisis (NPH1) and adolescentnephronophthisis (NPH3) share
the same characteristic renalmorphology, consisting of tubular basement
membrane changes,tubular atrophy and dilation, sclerosing tubulointerstitial
nephropathy,and cysts located predominantly at the corticomedullary junction.
However,a gene locus for NPH1 (median age at end-stage renal disease[ESRD],
13.1 yr) was localized to 2q12 to q13, and the responsiblegene NPHP1
was found to be homozygously deleted in 70 to 80%of NPH1 patients
(3,4).
In contrast to NPH1, patients with NPH3reach ESRD significantly later with a
median age of 19 yr (range,12 to 47 yr), thus rendering NPH3 the recessive
renal cysticdisease with the latest onset of ESRD
(2). The best animal modelfor
this disease seems to be the pcy mouse model for late-onset
polycystickidney disease, because inheritance is recessive, renal pathology
resemblesthat of NPH3, and ESRD is reached in adult mice. To study whether
bothdiseases might be homologous, we compared phenotypic and geneticfindings
in both diseases. By a physical mapping strategy, wecloned the NPHP3
region, mapped several expressed genes, andwere able to demonstrate by
mapping data that NPHP3 and pcyare syntenic. This is the
first example of synteny between ahuman renal cystic disease and a
spontaneous renal cystic mousemodel. By fluorescence in situ
hybridization, we were able toassign the chromosomal region of the human
NPHP3 locus to chromosome3q21 to 3q22. In addition, by haplotype
analysis in the largeVenezuelan kindred with NPH3
(2), we identified two patients
withNPH3 not reported previously. The identification of asymptomaticand
symptomatic probands who carry the homozygously affectedhaplotype enabled us
to study the disease phenotype of NPH3at different stages of the disease.
Physical Mapping
A set of 19 yeast artificial chromosomes (YAC) potentially residingat
human chromosome 3q21 to q22 was derived from the informationavailable in the
public database of the Whitehead Institute(http://www-genome.wi.mit.edu). YAC
clones were obtained fromCentre d'Etude du Polymorphisme Humain (CEPH; Paris,
France).Several polymorphic markers, sequence-tagged site (STS) markers,and
expressed sequence-tagged site (EST) markers, presumablyresiding in the
region of interest, were analyzed by PCR amplificationindividually for
positivity with YAC clones by STS content mapping.Information for the
examined markers concerning PCR primers,conditions, and location were
retrieved through public databases(Whitehead [http://www-genome.wi.mit.edu],
Cooperative HumanLinkage Center [http://www.chlc.org], Genome database
[http://www.gdb.org],Gene Map 99 [http://www.ncbi.nlm.nih.gov/genemap]).
Inter-AluPCR was performed using YAC clones 951a4 and 858b8 as templates
(5).PCR products were used as
probes for hybridization to screenthe Peter de Jong P1 artificial chromosome
(PAC) library (6).Bacterial
artificial chromosome (BAC) libraries CEPH B and ResearchGenetics RB
(Research Genetics, Huntsville, AL) were screenedfor STS content. BAC/PAC
clones were tested by STS content mappingwith the above markers. BAC/PAC ends
were sequenced, and PCRprimers for clone-end markers were generated. For STS
contentmapping, one individual colony was picked for each YAC, PAC,or BAC
clone. One colony was suspended in 200 µl of sterilewater. Ten µl of
each sample were dried in a microtiterplate, followed by one negative control
(water for template)and one positive control (10 to 30 ng of genomic DNA of a
healthyindividual). PCR was performed with dry template, 6 to 18 pmolof
primers, 0.2 mM each dATP, dCTP, dGTP, and dTTP, 10 mM Tris-HCl(pH7.3), 50 mM
KCl, 0.001% gelatin (w/vol), and 0.3 U of Thermusaquaticus DNA
polymerase (Perkin-Elmer Cetus, Norwalk, CT).Amplification was carried out
with denaturation at 94°Cfor 30 s, annealing at 53 to 60°C for 30 s,
extension at72°C for 60 s, and 32 cycles. PCR products were separatedby
electrophoresis in a 1% agarose gel. The gels were stainedwith ethidium
bromide and photographed. Each result was confirmedat least once. BAC/PAC
ends were directly sequenced using theBig dye sequencing system (ABI-377,
Perkin-Elmer Cetus), andPCR primers for clone-end markers were generated.
Human-Mouse Synteny Analysis
On the basis of the physical mapping data obtained with thestudies
described above and on the basis of physical mappingdata from the Mouse
Genome Project (data obtained from http://www.jackson.org),we performed a
human-mouse synteny analysis using for DNA sequencecomparison the BLAST-N
subroutine (7). The
pcy locus has beenmapped to mouse chromosome 9 and is flanked by
markers D9Mit16and D9Mit24
(8). Physical data for the
centromeric part of thiscritical region are available from the Whitehead
YAC-contigWC9.35 (http://www-genome.wi.mit.edu). We used all mouse STSand
EST sequences of that contig and performed BLAST-N analysis.If no sequence
similarity to any human EST/gene was obtained,we conducted a BLAST-N analysis
to identify a murine EST cluster.This EST cluster was again used for BLAST
analysis to identifyhomologous human EST or genes.
Fluorescence In Situ Hybridization
Metaphases were harvested after direct preparations of short-termcultures
(24 to 48 h) of phytohemagglutinin-stimulated normalperipheral blood
lymphocytes. Methods of cell culture, chromosomepreparation, and staining by
a modified GAG banding techniquehave been described previously
(9,10).
Chromosomal bands wereclassified according to the International System for
CytogeneticNomenclature (ISCN, 1995). After fixation in methanol:aceticacid
3:1, the cells were air dried on glass slides and frozenat -20°C for at
least 1 d. PAC/BAC DNA of clones RB815E10,874N07, 544P15, 967G23, 156M15, and
286D11, which are locatedwithin the critical genetic NPHP3 region
(for exact locationof the probes, see
Figure 1) was labeled with
Texas Red (MolecularProbes, Göttingen, Germany)
using a nick translation kit(Vysis, Bergisch Gladbach, Germany). Ten ng of
labeled DNA wasdissolved in 10 µl of hybridization solution consistingof
50% formamide, 10% dextran sulfate, 1 x SSC, 500 ng of Cot-1DNA, and 5
µg of sonicated salmon sperm DNA and then denaturedat 95°C for 5 min.
Slides with metaphase spreads of normalhuman controls were denatured in 70%
formamide/2 x SSC at 72°Cfor 3 min on a heating plate and
subsequently passed througha graded ethanol series. The slides were
counterstained with4,6-diamino-2-phenylindol (2 mg/ml) and mounted in
anti-fadesolution (90% glycerol, 10% phosphate-buffered saline, 1 mg/ml
phenylenediamine).Metaphases were analyzed using Zeiss Axiophot
epifluorescencemicroscope equipped with filter combination 1 according to
Pinkeland a cooled charge-coupled device camera (Metasystems, Altlussheim,
Germany)was used. TexasRed and 4,6-diamino-2-phenylindol fluorescencewere
recorded separately as gray-scale images by changing theexcitation wave
length only while the beam splitter and emissionfilter remained in position.
The images were then pseudocoloredand were merged using a digital image
analysis software program(ISIS, Metasystems).
Figure 1. Physical map of the human NPHP3 (a through c) and the mouse
pcy (d) loci. (a) Polymorphic markers and sequence-tagged sites in
the NPHP3 region. Flanking markers are D3S1292 and D3S1238. Gene
symbols are given in parenthesis. Expressed sequence-tagged sites (EST) are
shown in italics. (b) Complete yeast artificial chromosomes (YAC) contig
generated in the region. Sequence-tagged site (STS) content for markers in (a)
is indicated by vertical lines and dots on YAC clones. (c) PAC and BAC in the
region. STS content for markers in (a) is indicated by vertical lines and
triangles. PAC or BAC with asterisks were studied by fluorescence in
situ hybridization (FISH) and are located on human chromosome 3q21 to
q22. (d) Whitehead YAC contig (WC9.35) on mouse chromosome 9 of the
pcy locus with EST markers showing homology to genes identified in
the human NPHP3 region. The minimal syntenic region of NPHP3
and pcy is shown hatched. The centromeric (cen) to telomeric (tel)
orientation is indicated.
Clinical Studies
In the large Venezuelan kindred with NPH3
(2), blood samplesfrom 13
probands who had not been studied previously were obtainedon the basis of
informed consent. Haplotype analysis with microsatellitesfrom the
NPHP3 region was performed as described previously
(2).All probands were studied
by measurement of serum creatinine,hemoglobin level, and urinalysis. Renal
ultrasound was performedin probands ID202 and ID213 carrying the homozygously
affectedhaplotype diagnostic for NPH3. In proband ID202, maximum urine
concentrationcapacity was tested by a 12-h water deprivation test. Serumand
urine osmolarity were measured at 0 and 12 h of the test.In proband ID213,
who presented in chronic renal failure, renalbiopsy was performed and
evaluated using standard histopathologystaining procedures.
Physical Mapping
We generated a complete YAC contig spanning the whole criticalregion of
NPH3, thereby cloning the NPHP3 critical genetic region
(Figure 1, a and b).The
critical disease interval is flanked by thecentromeric marker D3S1292 and the
telomeric marker D3S1238.The maximum physical distance for the two markers
that flankthe NPHP3 region as defined by the combined length of
clones951a4 and 858b8 is 3.3 Mb. We thereby restricted the physicalinterval
for NPHP3 to less than 3.3 Mb
(Figure 1b). We physically
localizedseven expressed genes (ACPP [phosphatase, prostate-specific
acid],TOPB1 [topoisomerase (DNA) II binding protein], EDF1
[endothelialdifferentiation-related factor 1], TF [transferrin],
DGKZ [diacylglycerolkinase-zeta], SLC21a2 [prostaglandin
transporter, PGT], RYK[receptor-like tyrosine kinase]), eight EST,
seven microsatellites,and three STS markers within the critical disease
interval forwhich previously no physical location was known.
Human-Mouse Synteny Analysis
Human-mouse synteny analysis was performed on the basis of expressedgenes
localized to the YAC/PAC/BAC contig generated. Four murineEST residing on
Whitehead YAC contig WC9.35 within the pcy criticaldisease interval
showed a very high degree of sequence similaritywith human genes/EST of the
critical region of NPHP3 (see
Figure 1d).The order of the
four genes/EST was found to be conservedbetween human and mouse. This high
degree of continuous sequencesimilarity gives evidence that human
NPHP3 and murine pcy mapto syntenic genetic regions
(Figure 1). For results of
BLASTanalysis, see Table
1.
Table 1. Results of sequence similarity analysis using murine EST and genes
located in the vicinity of the pcy locusa
Fluorescence In Situ Hybridization
Fluorescence in situ hybridization (FISH) analysis with clonesRB815E10,
874N07, 544P15, 967G23, 156M15, and 286D11 that arelocated within the
critical disease interval of NPHP3
(Figure 1)revealed positive
signals only for human chromosome 3q21to q22. To illustrate these data, the
results from FISH analysisusing PAC 286D11 is shown in
Figure 2.
Figure 2. FISH mapping of PAC clone 286D11 (alias D11286) on human chromosome 3q21 to
q22.
Clinical Studies
From the 13 probands studied, we identified 2 probands witha homozygously
affected haplotype diagnostic for NPH3
(Figure 3).Laboratory
investigations and haplotypes for the other 11probands were normal. Proband
ID202 was a 12-yr-old girl withoutany clinical complaints. Laboratory
investigations includingmaximum urine concentration capacity were normal.
Ultrasoundof her kidneys revealed multiple small cysts measuring
approximately0.5 cm in diameter at the corticomedullary junction. The male
probandID213 presented with polyuria and loss of appetite at the ageof 27
yr. His serum creatinine was 18.8 mg/dl. Within 1 mo ofclinical presentation,
renal replacement therapy had to be implemented.Ultrasound examination of the
kidney revealed multiple cystsin both kidneys. The cysts were predominantly
located at thecorticomedullary junction but also elsewhere in the kidney
(Figure 4, a and b).Histology
showed typical findings for NPH3 consistingof tubular basement membranes
changes with segments of thickening,thinning, folding and a multilayered
appearance, tubular atrophyand dilation, mononuclear infiltrates and diffuse
interstitialfibrosis, and concentric periglomerular fibrosis with thickening
ofBowman's capsule (Figure
4d). Ultrasound findings and histologicfindings in patient ID213
were compared with findings from macroscopicand microscopic anatomy in the
pcy mouse (Figure 4).
Figure 3. Haplotype analyses of new probands ID213 and ID202 from the large
Venezuelan adolescent nephronophthisis (NPH3) kindred. Note that both probands
homozygously share the same haplotype that is associated with the affected
status of the Venezuelan kindred studied
(2). For comparison, haplotypes
of three previously reported individuals are shown, one affected proband and
one obligate carrier, in whom recombinations for markers D3S1292 and D3S1238,
respectively, define the critical region of NPH3 (underlined). The centromeric
(cen) to telomeric (tel) orientation is indicated.
Figure 4. Renal ultrasound of proband ID213 showing a right kidney (A) with a length
of 7.6 cm and a left kidney (B) measuring 8.3 cm. Kidneys have increased
echogenicity and multiple cysts ranging in size from 0.2 to 2.0 cm in
diameter. (C) Cross section of a 2-wk-old pcy mouse showing cysts located
predominantly at the corticomedullary junction and in the medulla. (D)
Silver-methenamine trichrome staining of a renal biopsy of proband ID213 with
typical findings for NPH3 consisting of tubular basement membranes changes
with segments of thickening, thinning, folding and a multilayered appearance,
tubular atrophy and dilation, mononuclear infiltrates, and diffuse
interstitial fibrosis. (E) Periodic acid-Schiff staining of renal specimen of
a 2-mo-old pcy mouse exhibiting similar findings as observed in NPH3,
consisting of tubular atrophy and dilation, mononuclear infiltrates, and
diffuse interstitial fibrosis.
NPH3 was only recently identified as a novel type of NPH ina large
Venezuelan inbred kindred (2).
ESRD is reached in NPH3at a median age of 19 yr, indicating that this disease
has alate onset of ESRD, when compared with other recessive renalcystic
diseases such as infantile and juvenile NPH and autosomal-recessivepolycystic
kidney disease
(11,12,13).
We previously localizedthe gene locus (NPHP3) of NPH3 to a 2.4-cM
interval on chromosome3q applying a homozygosity mapping strategy in a large
Venezuelankindred (2).
To identify the responsible gene NPHP3, we cloned the critical
NPHP3region in a complete YAC and partial PAC/BAC contig and
physicallylocalized several genes/EST within the region of interest. The
maximumlength of the critical NPHP3 region is less than 3.3 Mb and
correspondsto the combined length of clones 951a4 and 858b8. By FISH analysis
usingPAC/BAC clones evenly distributed within the critical regionof
NPHP3, we cytogenetically localized the gene locus to chromosome3q21
to q22 (Figure 2). On the basis
of these human physicalmapping data of the critical NPHP3 region, a
human-to-mousesynteny analysis was performed and allowed definition of
syntenyfor NPHP3 and a genetic region on mouse chromosome 9
(Figure 1).How far the area of
synteny reaches centromeric toward humanchromosome 3q21 or murine chromosome
9tel, respectively, cannotbe discerned because no additional mouse physical
data are availablefor that region. It is interesting that the genetic region
onmouse chromosome 9 contains the polycystic kidney disease (pcy)
locus,which was previously mapped to mouse chromosome 9 flanked byD9Mit16
and D9Mit24 (8). Thus, we
demonstrate synteny betweenthe human NPHP3 and the murine cystic
kidney disease locus pcy(Figure
1). To our knowledge, this is the first report of syntenybetween
a human and a spontaneous mouse cystic kidney diseaselocus. Among recessive
mouse models of renal cystic disease,pcy is the mouse model with the most
slowly progressing adult-typeform of polycystic kidney disease
(14,15),
thus resembling thelate manifestation of NPH3. Disease traits in pcy and NPH3
sharethe same autosomal-recessive inheritance pattern. By back-crossingthe
affected pcy gene to different mouse strains, a variationof the
severity of the pcy phenotype in relation to differentgenetic backgrounds was
noted (16). Subsequently, two
modifierloci on mouse chromosomes 4 and 16 were identified by linkage
analysis(17). The presence of
modifier genes could also serve to explainthe wide age range (12 to 47 yr) of
ESRD observed in NPH3. Comparisonof NPH3 and pcy revealed several phenotypic
similarities, including(1) mode of inheritance, (2 late
disease manifestation, (3)renal cyst location at the
corticomedullary junction, (4) lackof extrarenal disease
manifestations such as hepatic disease,and (5) histology (see also
Table 2). There was, however, a
dissimilaritywith respect to renal enlargement and cerebral vascular
aneurysmspresent in pcy but not in NPH3.
Table 2. Comparison of clinical, pathological, and genetic findings of
adolescent NPH and polycystic kidney disease in mice (pcy)a
Because all reported patients with NPH3 presented already inESRD, only
little is known about the disease before renal failure.Therefore, we screened
new relatives of the large Venezuelankindred with NPH3, reported previously
(2). We identified a12-yr-old
girl with no clinical symptoms, who carries a homozygouslyaffected haplotype
for markers from the NPHP3 region
(Figure 3).This enabled us to
study the disease phenotype of NPH3 beforerenal failure. Laboratory
investigations including urine concentrationcapacity were normal. Because in
ID202 renal sonography showedcysts at the corticomedullary junction, renal
cyst developmentat the corticomedullary junction seems to be an early sign of
NPH3in this proband. The other proband who was diagnosed as havingNPH3 was
27 yr old and presented with clinical and laboratoryfindings of chronic renal
failure (Figure 3). Ultrasound
ofhis kidneys showed multiple cysts throughout the entire kidneybut
predominantly located at the corticomedullary junction
(Figure 4).In pcy, cysts tend
to develop primarily at a similar sitein the kidney
(Figure 4). Takahashi et
al. (15) noted in
DBA/2-pcy/pcymice by 4 wk of age a well-delineated cyst in the outer portion
ofthe inner medulla in almost every sample examined, and in thelatest stages
of the disease (30 wk and older) the whole kidneywas enlarged and dominated
by cysts. Therefore, early cyst developmentseems to be an early sign of NPH3
and pcy. It is interestingthat histopathologic changes observed in NPH3 and
pcy show similarities(Figure 4, d and
e), consisting of predominant dilation of distaltubules and
collecting ducts, sporadic dilation of Bowman'scapsule, and interstitial
inflammatory infiltrates causing achronic sclerosing tubulointerstitial
nephropathy
(2,15).
Inaddition, tubular basement membrane changes with local attenuation,
thickening,and multilayering, which are supposed to be characteristic
findingsin adolescent and juvenile NPH, can also be observed in pcymice
(2,15,18,19).
On the basis of genetic and phenotypic findings, NPH3 and murinepcy most
likely are caused by recessive mutations of homologousgenes. This will help
to accelerate gene identification of NPH3and pcy because the search for the
responsible genes shouldbe focused to the critical genetic region that
overlaps in bothdiseases, which is flanked by D3S1292 and SGC3327
(TF). Consideringall EST and genes localized within this interval,
only EDF1and TOPB1 show a broad expression pattern,
including kidneysimilar to the expression pattern of NPHP1
(20, thus renderingthem
potential candidate genes (http://www.ncbi.nlm.nih.gov/UniGene).If homology
of NPH3 and pcy is confirmed by gene identification,this will, in addition,
have clinical implications, becauseintervention studies in pcy mice have
demonstrated beneficialeffects by modification of protein intake and
administrationof methylprednisolone
(21,22,23,24).
Acknowledgments
H.O. and F.H. were supported by a grant of the German ResearchFoundation
(DFG Om 6/1-1; DFG Hi 381/3-3) and by a grant fromthe Zentrum Klinische
Forschung, Freiburg (ZKF-A1). The excellenttechnical assistance of Martina
David is gratefully acknowledged.
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Received for publication April 17, 2000.
Accepted for publication June 1, 2000.
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Abstract
Introduction
