#173900 POLYCYSTIC KIDNEYS
Alternative
titles; symbols
POLYCYSTIC KIDNEY DISEASE; PKD
POLYCYSTIC KIDNEY DISEASE, ADULT, INCLUDED; APKD,
INCLUDED
POTTER TYPE III POLYCYSTIC KIDNEY DISEASE,
INCLUDED
table OF
CONTENTS
Gene Map Locus: 16p13.3-p13.12
Note: pressing the 
symbol will find the citations in MEDLINE whose
text most closely matches the text of the preceding
OMIM paragraph, using the Entrez MEDLINE
neighboring function.
TEXT
A number sign (#) is used with this entry
because of evidence that polycystic kidney disease
(PKD) may arise from mutations in any of several
human disease loci; see PKD1 (601313)
and PKD2 (173910)
for descriptions of genes on chromosomes 16 and 4.
See also the PKD3 locus (600666).
DESCRIPTION
- Adult polycystic kidney disease is an
autosomal dominant disorder with the cardinal
manifestations of renal cysts, liver cysts, and
intracranial aneurysm. Genetic heterogeneity is
recognized, with one locus (PKD1), responsible
for the most common form, being tightly linked
to markers on the extreme distal portion of 16p
in the region of the alpha-hemoglobin locus.
Using a PKD1 patient with a chromosome
translocation, the European
Polycystic Kidney Disease Consortium (1994)
isolated a novel gene called PBP and detected
deletion and splicing mutations associated with
independent PKD1 patients.
-
NOMENCLATURE
- Polycystin-1 (601313)
and polycystin-2 (173910)
are appropriate designations for the proteins
encoded by genes on 16p and 4q and mutant in
PKD1 and PKD2, respectively.
-
CLINICAL
FEATURES
- The phenotypic variability in APKD involves
differences in the rate of loss of glomerular
filtration, the age of reaching end-stage renal
disease (ESRD), and the occurrence of
hypertension, symptomatic extrarenal cysts, and
subarachnoid hemorrhage from intracranial
'berry' aneurysm.
Kidney
Age at onset of renal failure is variable,
even within families. Shokeir
(1978) described families with typical adult
cystic kidney disease in which single
individuals died early in life from polycystic
renal disease. Zerres et
al. (1985) suggested that early
manifestation of APKD may aggregate in families
because of genetic modifier(s). They diagnosed
such a case in utero by ultrasound. A brother
and a cousin also had early manifestation.
Reeders (1986)
described a phenomenal family ascertained
through a fetus found incidentally on
ultrasonography to have polycystic kidney
disease. Adults had more conventional PKD in an
autosomal dominant pedigree pattern. This is a
situation comparable to the ascertainment of
familial tuberous sclerosis by the finding of
cardiac rhabdomyomata on prenatal
ultrasonography (see 191100).
Among 321 offspring of probands with
polycystic kidney disease, Ravine
et al. (1991) identified 68 (21%) who had
ultrasound evidence of polycystic kidney
disease. Of this previously undiagnosed group,
25 (37%) had one or more treatable complications
at the time of diagnosis, including 20 cases of
hypertension, 7 cases of impaired renal
function, and 4 cases of bacterial urinary tract
infection. The findings underscored the
importance of screening at-risk family members.
In 13 large Spanish families, Coto
et al. (1992) found that all subjects over
the age of 30 who were shown by linkage to carry
the mutation had renal cysts by ultrasonography,
whereas 40% of carriers of the mutation younger
than 30 did not have renal cysts. Hypertension
was found to be more frequent in those with
renal cysts.
Wirth et al.
(1987) studied 6 kindreds in which
polycystic kidney disease had early onset with
cystic enlargement of the kidneys detected by
prenatal sonography in some cases and with death
soon after birth in several. Linkage analysis
indicated that the gene locus mutant in these
families is the same as that in standard
adult-onset cases, i.e., the locus on chromosome
16p.
Jeffery et al.
(1998) presented a family with adult-onset
autosomal dominant polycystic kidney disease in
2 generations, linked to the PKD1 locus and with
paternal transmission to the fetus. The fetus
carried the PKD1 haplotype and was, therefore, a
gene carrier. Progressive hyperechogenic renal
enlargement, but no cysts, was documented by
serial fetal ultrasounds at 21, 23, and 34 weeks
of gestation. Unexpectedly, the newborn renal
scan showed normal-sized kidneys with apparently
normal corticomedullary differentiation.
However, at 11 months of age, the evolution of
cysts in 1 kidney, and then in the other kidney
at 20 months, was documented by ultrasound in
the absence of clinical symptoms or signs.
Germino (1998)
indicated that approximately 50% of polycystic
kidney disease leads to ESRD and that 4 to 5% of
ESRD is due to PKD. The kidneys may achieve an
enormous size, approximately 50 pounds in the
case of a woman 62 inches tall.
Gastrointestinal
Dalgaard (1963)
found liver cysts in 43% of 173 autopsied cases
in Denmark. In a review of cases, largely from
the literature, Poinso et
al. (1954) found that polycystic kidneys
occurred in 53% of 224 cases of polycystic
livers. Dalgaard
(1963) said he had found a regular
transition from polycystic liver degeneration to
the solitary liver cyst in association with
polycystic kidney. Ellis
and Putschar (1968) presented the case of a
42-year-old woman with polycystic kidneys and
portal hypertension for which splenorenal shunt
was performed. Liver biopsy showed 'disseminated
microcystic biliary hamartomas, with congenital
fibrosis.' The mother died with hypertension,
renal disease, and stroke at age 64. Two of her
sisters died of renal disease. Two sisters of
the proband were said to have polycystic kidney
disease. Congenital hepatic fibrosis may occur
with normal kidneys or with a variety of renal
malformations, most often ectatic renal tubules
resembling medullary sponge kidneys (see
polycystic kidney, infantile, type I, 263200).
Terada and Nakanuma
(1988) demonstrated nonobstructive diffuse
dilatation of intrahepatic bile ducts in 3
autopsy cases of autosomal dominant adult
polycystic disease. Meyenburg complexes and
liver cysts not communicating with the biliary
tract lumen were also seen. Jordon
et al. (1989) described the very rare
association of Caroli disease with adult-type
polycystic kidney disease. Caroli disease is a
rare form of fibropolycystic disease of the
hepatobiliary system characterized by segmental
cystic dilatation of intrahepatic ducts and
associated with intrahepatic cholelithiasis,
cholangitis, and hepatic abscesses. It is found
more commonly with other forms of cystic renal
disease (see 263200).
Telenti et al. (1990)
reviewed 5 cases of infected hepatic cyst in
polycystic kidney disease together with 9
reported cases. Clinical and laboratory features
and the use of scanning techniques facilitated
diagnosis. The treatment of choice was a
combination of percutaneous drainage and
antimicrobial therapy.
Scheff et al.
(1980) pointed out the high incidence of
diverticulosis and diverticulitis in patients
with chronic renal failure from polycystic
disease. Colonic diverticula affect about 80% of
patients with end-stage renal disease (Scheff
et al., 1980), and colonic perforation is
rather frequent in these patients.
Involvement of the liver is more frequent,
more striking, and earlier in onset in females
than in males (Germino,
1998).
Cerebrovascular and
Cardiovascular
Ditlefsen and Tonjum
(1960) described a family in which there
were 15 verified and 2 suspected cases of
polycystic kidney disease. Six of the patients
suffered from cerebral hemorrhage. In 1 of the
6, aneurysm of the middle cerebral artery was
verified. Intracranial 'berry' aneurysm is a
rather frequently associated malformation.
Levey et al. (1983)
used decision analysis to assess whether
patients with polycystic renal disease should
have routine cerebral arteriography for
intracranial aneurysms and prophylactic surgery
if an aneurysm is detected. They concluded 'no'
because the benefit exceeds 1 year only if the
prevalence of aneurysm exceeds 30%, the surgical
complication rate is 1% or less, and the patient
is under 25 years of age. Newer noninvasive
tests, such as digital-subtraction angiography,
may change this decision.
To determine the prevalence of intracranial
aneurysms, Chapman et al.
(1992) studied 92 subjects with autosomal
dominant polycystic kidney disease who had no
symptoms or signs of any neurologic disorder.
High-resolution computed tomography (CT) was
performed in 60 subjects, 4-vessel cerebral
angiography in 21, and both procedures in 11. In
4 of the 88 subjects in whom the radiologic
studies were successfully completed,
intracranial aneurysms were found, as compared
with the prevalence of 1% reported for an
angiographic study of the general population.
Multiple aneurysms were found in 3 of the 4
subjects. Chapman et al.
(1992) concluded that an increased frequency
of asymptomatic intracranial aneurysms occurs
with polycystic kidney disease, although the 95%
confidence interval for their finding (0.1 to
9%) included the possibility of no difference
from the prevalence of 1% reported in the
general population. They recommended
high-resolution CT as a screening test.
Chapman and Hilson
(1980) suggested a relationship between
polycystic kidneys and abdominal aortic
aneurysm. Of 31 patients on chronic dialysis for
polycystic kidneys, 3 had aortic aneurysm.
Torra et al. (1996)
examined this question in detail by means of a
sonographic study of the abdominal aorta in 139
ADPKD patients and in 149 healthy family
members. In both groups, an increase in aortic
diameter related to age and sex was found, the
aortic diameter being wider in older men than in
women. In ADPKD patients, neither a wider aortic
diameter nor a higher prevalence of abdominal
aortic aneurysms could be found in any age
group. They concluded that, although these
patients are prone to develop aortic aneurysms
because of hypertension and possibly associated
connective tissue disorders, abdominal aortic
aneurysm does not appear to be a frequent
feature.
Hossack et al.
(1988) used echocardiography, including
Doppler analysis, to assess the prevalence of
cardiac abnormalities in 163 patients with
autosomal dominant polycystic kidney disease,
130 unaffected family members, and 100 control
subjects. In these 3 groups the prevalence of
mitral valve prolapse was 26, 14, and 2%,
respectively. A higher prevalence of mitral
regurgitation, aortic regurgitation, tricuspid
regurgitation, and tricuspid valve prolapse was
also found in the patients with polycystic
kidney disease. Hossack
et al. (1988) interpreted these findings as
reflecting the systemic nature of polycystic
kidney disease and supporting the hypothesis
that the disorder results from a defect in the
extracellular matrix and that the cardiac
abnormalities are an expression of that defect.
A combination of hypertension and fundamental
defect may be involved in the occurrence of
dissecting aneurysm of the aorta, as described
in an African-American man in his twenties
(Germino, 1998). (The
patient had a history of PKD and was known to
have hypertension at the age of 18 years, 2
intracranial aneurysms at the age of 24 years,
and dissecting aneurysm at the age of 27 years.)
Both intracranial and aortic aneurysm appear to
cluster in families.
Miscellaneous
Emery et al.
(1967) observed the coincidence of myotonic
dystrophy (160900)
and polycystic kidneys in at least 3 members of
a family.
Zerres et al.
(1984) gave a comprehensive review of all
forms of cystic kidney disease. They suggested
that since the Potter type III is
pathogenetically and genetically heterogeneous,
the term should not be used synonymously for
autosomal dominant polycystic kidney disease.
Zerres et al. (1985)
pointed out that patients on long-term renal
hemodialysis develop cystic kidneys that can be
nearly impossible to distinguish from autosomal
dominant cystic kidney disease. Gabow
(1993) reviewed all aspects of the genetics,
pathogenesis, clinical manifestations, and
diagnosis of autosomal dominant polycystic
kidney disease. She indicated that approximately
50% of patients have hepatic cysts and that
these increase with age. Hypertension affects
more than 80% of patients with end-stage renal
disease. Renal failure is estimated to affect
45% of patients by the age of 60.
In the 10 families with a PKD1 mutation
(i.e., linked to markers on chromosome 16)
reported by Parfrey et
al. (1990), 46% of the members less than 30
years old who had a 50% risk of inheriting a
mutation had renal cysts, as compared with 11%
of such members in the 2 families without
linkage (P less than 0.001). In the PKD1
families, all 67 diagnoses made by
ultrasonography were confirmed by determination
of the genotype as inferred from linkage. Of the
48 members less than 30 years old who inherited
the PKD1 mutation, 40 had renal cysts. All 27
members 30 years old or older who inherited the
mutation had renal cysts, suggesting that the
probability of a false-negative diagnosis did
not exceed 0.13 in this age group. The mean age
at onset of end-stage renal disease among
members of the PKD1 families was 56.7 +/- 1.9
years, as compared with 69.4 +/- 1.7 years among
members of the unlinked families (P = 0.0025).
Hypertension and renal impairment were less
frequent and occurred later in the families
without the PKD1 mutation.
In a survey in France involving 889 affected
subjects, Simon
(1995) found no difference in the cumulative
survival to end-stage renal disease between
males and females. By the age of 50 years, 22%
of the patients had ESRD, by the age of 58, 42%,
and by the age of 73, 72%. They found that males
under 65 years of age have a rate of progression
toward renal failure that is significantly more
rapid than in females of the same age group. The
risk linked to gender disappeared after 65 years
of age.
Somlo et al.
(1993) described a family in which an
overlap connective tissue disorder (OCTD)
cosegregated with the chromosome 16-linked form
of APKD. The connective tissue phenotype in this
family included aortic root dilation, aortic and
vertebral artery aneurysms with dissection, and
aortic valve incompetence, as well as pectus
abnormalities, pes planus, joint laxity,
arachnodactyly, scoliosis, dolichostenomelia,
and high arched palate. Two markers flanking the
PKD1 region were tightly linked to both APKD and
OCTD, whereas there was no evidence for linkage
with either fibrillin gene FBN1 on chromosome 15
or FBN2 on chromosome 5. Perrone
(1997) led a discussion of extrarenal
manifestations of ADPKD. The increased frequency
of diverticular disease was reviewed, including
the increased risk of colonic perforation after
renal transplantation. The mechanism of this, as
well as other extrarenal complications, is
unclear.
MAPPING
- Chanmugam et al.
(1971) reported a family that might suggest
linkage of hereditary spherocytosis (182900)
and polycystic kidney disease. A father and 3
children had both diseases. Three other children
and 4 sibs of the father were thought to be free
of both diseases. There is, however, no other
suggestion of location of a spherocytosis locus
on chromosome 16, or chromosome 4 (cf. 173910),
where genes for adult polycystic kidney disease
have been mapped.
Reeders et al.
(1985) showed that the PKD1 locus is closely
linked to the alpha-globin locus (141800)
on 16p (lod = 25.85, theta = 0.05, 99%
confidence limits = 2-11 cM). In establishing
this linkage, they used a highly polymorphic
region about 8 kb beyond the 3-prime end of the
alpha-globin cluster (3-prime-HVR =
3-prime-hypervariable region). In the Oxford
data (Reeders, 1985),
APKD versus phosphoglycolate phosphatase
(172280)
showed a lod score of 8.21 at theta = 0.0. PGP
and HBA showed a lod score of 11.61 at theta =
0.0. In 13 South Wales kindreds, Lazarou
et al. (1987) found a maximum lod score of
24.187 at a recombination fraction of 0.03 for
linkage between PKD1 and alpha-globin. Despite
phenotypic heterogeneity, they found no evidence
of linkage heterogeneity.
Watson et al.
(1987) found tight linkage of APKD and PGP;
the maximum likelihood value of the
recombination fraction was 0.0 with a lod score
of 5.5. Together with the APKD versus HVR
linkage data, these findings may indicate that
APKD and PGP are on the 5-prime side of the
alpha-globin cluster. The polarity of the HBAC
viz-a-viz the centromere is unknown. The
recombination fraction for the 3-prime-HVR and
APKD is somewhat greater in males than in
females (Reeders,
1986)--an anomalous finding. Reeders
et al. (1985) found no definite
recombination between PGP and APKD. HBAC is
distal to APKD but whether PGP is proximal or
distal to APKD is unknown. The evidence on
location of HBAC is conflicting, with
assignments from 16p13.11 to 16p13.33. Reeders
et al. (1988) described an array of linked
markers that bracket the PKD1 locus. Germino
et al. (1990) demonstrated a DNA marker,
D16S84, that showed no recombination with PKD1
in 201 informative meioses.
Pound et al.
(1992) presented evidence for linkage
disequilibrium between PKD1 and D16S94.
Breuning et al. (1990)
further defined the location of markers on 16p
in the vicinity of the PKD1 locus. Harris
et al. (1991) identified closely linked
microsatellite polymorphisms that could be used
in a PCR-based assay for a rapid, inexpensive,
and nonradioactive method of linkage analysis.
Gal et al. (1989)
studied 10 families in which early manifestation
of the disorder was a frequent finding. In all
families studied, close linkage was observed
between the chromosome 16 alpha-globin marker
and the APKD locus. They concluded that there is
no evidence for genetic heterogeneity of APKD in
families with early- and later-onset disease. In
28 northern European pedigrees from England,
Scotland, Holland, and eastern Finland,
Reeders et al. (1987)
found no evidence of heterogeneity of the
linkage of PKD1 with alpha-globin. (The
recessive form of early-onset polycystic kidney
disease is probably not linked to HBA (Reeders,
1986).)
Zerres et al.
(1993) also investigated 79 children with
early manifestation of autosomal dominant
polycystic kidney disease. They belonged to 64
families (64 index patients and 15 affected
sibs). Early manifestation was defined as
clinical manifestations (hypertension,
proteinuria, impaired renal function, palpably
enlarged kidneys) occurring before the age of 15
years. A strong familial clustering for early
manifesting ADPKD was found; out of the total of
65 sibs of the 64 index patients, 15 showed
comparably early manifestation. Another 10
symptom-free children were diagnosed
sonographically as having ADPKD before the age
of 18 years. The authors noted that high
recurrence risk to sibs has important
implications for genetic counseling and clinical
care of affected families.
Among the same 17 families reported by Bear
et al. (1984,
1992), Parfrey
et al. (1990) found that polycystic kidney
disease cosegregated with polymorphic DNA
markers flanking the PKD1 locus in 10; in 2
families cosegregation did not occur, and in 5
families linkage could not be determined because
of uninformativeness of the markers.
Ryynanen et al.
(1987) did linkage studies in a 4-generation
Finnish family with polycystic kidney disease;
all affected members of the extended pedigree
were asymptomatic and none had developed renal
failure. They showed that the mutation in this
family was closely linked to the alpha-globin
cluster. This might be an allelic disorder.
Using DNA from a set of multigenerational
families from CEPH (Centre d'etude polymorphisme
humaine, Paris), Keith et
al. (1987) constructed a genetic map of
chromosome 16 based on 40 polymorphic DNA
markers. The map spanned 142 cM in males,
somewhat larger than the 108 cM previously
estimated by chiasma counts. Males had higher
recombination fractions near the alpha-globin
gene cluster, but females showed higher
recombination in other regions.
Germino et al.
(1992) demonstrated that the PKD1 gene lies
within an extremely CpG-rich 750-kb segment of
16p13.3. Its genetic localization with respect
to physically mapped markers in this segment was
refined by Somlo et al.
(1992).
In the Spanish population, Peral
et al. (1993) typed 31 families from
different geographic areas using marker loci
flanking PKD1 on 16p. Multilocus linkage
analysis indicated that in 26 families the
disease resulted from PKD1 mutations, whereas in
3 families it resulted from mutations in a locus
other than PKD1; 2 other families were not
informative. Using the HOMOG test, they
estimated that PKD1-linked mutations were
responsible for 85% of families with PKD in
Spain.
See 173910
for a discussion of type II adult polycystic
kidney disease (PKD2), the gene for which maps
to chromosome 4.
MOLECULAR
GENETICS
- Harris et al.
(1990) found that the region around the PKD1
locus is unusually rich in CpG dinucleotides. In
a search for the gene that is mutant in
polycystic kidney disease, Gillespie
et al. (1991) concentrated on CpG islands in
a region between 2 markers that flank the PKD1
locus and are separated by less than 750 kb. One
of the genes so marked was isolated from HeLa
and cultured cystic kidney epithelial cell cDNA
libraries. It was found to encode a 155-amino
acid peptide having 4 putative transmembrane
domains. The corresponding transcript was found
in all tissues tested but was most abundant in
brain and kidney. The deduced amino acid
sequence showed 93% similarity to part of the
proton channel of vacuolar H(+)-ATPase. Because
of the possible role of a mutated proton channel
in the pathogenesis of cystic disease, Gillespie
et al. (1991) sequenced cDNAs corresponding
to both alleles of an affected individual but
found no differences in the deduced amino acid
sequence. Moreover, transcript size and
abundance were not altered in cystic kidney.
Reeders (1992) put
forward an interesting 2-hit mutational
hypothesis for PKD1. He pointed out the several
unusual features such as the absence of
detectable abnormalities in most nephrons; even
in the end-stage disease, less than 10% of the
roughly 1 million nephrons in each kidney
contain cysts. Furthermore, any segment of the
nephron, from the glomerulus to the collecting
duct, may harbor a cyst. The hypothesis suggests
that at the sites of cyst formation, a somatic
mutation occurs in the chromosome 16 that does
not carry the inherited mutation. A prediction
of the 2-hit model is that renal cysts will
occasionally be found in persons without an
inherited predisposition as a result of two
somatic mutations occurring in a single cell.
One or 2 renal cysts are a common radiologic
finding in the general population and the
probability of finding a cyst in an individual
does, as predicted, rise with age. The 2-hit
model predicts that the number of cysts would
increase with age in PKD1.
The European
Polycystic Kidney Disease Consortium (1994)
isolated a gene encoding a 14-kb transcript that
was disrupted by a chromosome translocation in a
family with PKD1. Indeed, the unusual Portuguese
family had both PKD and tuberous sclerosis
(TSC2; 191092),
which maps to the same region of 16p. The mother
had a balanced translocation, 46,XX
t(16;22)(p13.3;q11.21), which was inherited by
her daughter. The son, on the other hand, had an
unbalanced karyotype 45,XY with monosomy for
16pter-p13.3 as well as for 22pter-q11.21. This
individual had the clinical phenotype of
tuberous sclerosis which was thought to be due
to the fact that the TSC2 locus located within
16p13.3 was deleted in the unbalanced karyotype.
The mother and the daughter with the balanced
translocation had the clinical features of PKD1,
while the parents of the mother were
cytogenetically normal, with no clinical
features of tuberous sclerosis and no renal
cysts on ultrasound examination. The location of
the breakpoint in the balanced translocation was
more than 20 kb proximal to the TSC2 locus. The
consortium isolated a gene spanning the
breakpoint and designated it PBP (for
'polycystic breakpoint'). They then identified
mutations in the PBP gene in other patients with
PKD1. The first mutation found was a 5.5-kb
genomic deletion within the 3-prime end of the
PBP gene in an affected woman and in
paraffin-embedded tissue from her affected
father (deceased at the time of report). The
second rearrangement detected was a 2-kb genomic
deletion within the PBP gene which was found to
have a frameshift deletion of 446 bp (between
basepairs 1746 and 2192). This was a de novo
mutation. Sequencing of genomic DNA in another
patient demonstrated a G-to-C transition at the
+1 position of the splice donor site following
the 135-bp exon. The splicing defect resulted in
an in-frame deletion of 135 bp from the PBP
transcript (basepairs 3696 to 3831). A fourth
patient was described in which both the TSC2
gene and the PKD1 gene were deleted. Further
study indicated that the deletion extended over
approximately 100 kb and deleted most, if not
all, of the PKD1 gene. By 'zoo blotting,' the
consortium demonstrated that the PKD1 gene is
conserved in other mammalian species, including
horse, dog, pig, and rodents. No related
sequences were seen by hybridization at normal
stringency in chicken, frog, or fruit fly.
Wunderle et al.
(1994) pointed out that 3 explanations are
classically used to account for dominant
inheritance in a disorder such as PKD1:
haploinsufficiency, gain-of-function mutations
(including dominant negative effects), and 2-hit
mechanisms (a second somatic mutation being
required to give rise to defective cells).
The International
Polycystic Kidney Disease Consortium (1995)
reported the complete structure of the PKD1 gene
and its protein. The PKD1 transcript contains 46
exons. The 14.5-kb PKD1 transcript encodes a
4,304-amino acid protein that has a novel domain
architecture. The amino-terminal half of the
protein consists of a mosaic of previously
described domains, including leucine-rich
repeats flanked by characteristic cysteine-rich
structures, LDL-A and C-type lectin domains, and
14 units of a novel 80 amino acid domain. The
presence of these domains suggested that the
PKD1 protein is involved in adhesive
protein-protein and protein-carbohydrate
interactions in the extracellular compartment.
They proposed a hypothesis that links the
predicted properties of the protein with the
phenotypic features of autosomal dominant PKD.
Peral et al.
(1995) sought mutations in the PKD1 gene in
this disorder. Analysis of 3 regions in the
3-prime part of the gene revealed 2 mutations
that occurred by a novel mechanism. Both were
deletions (of 18 or 20 bp) within the same 75-bp
intron and, although these deletions did not
disrupt the splice donor or acceptor sites at
the boundary of the intron, they nevertheless
resulted in aberrant splicing. Two different
transcripts were produced in each case; one
included the normally deleted intron while the
other had a 66-bp deletion due to activation of
a cryptic 5-prime splice site. No normal product
was generated from the deletion-mutant gene.
Peral et al. (1995)
speculated that aberrant splicing probably
occurred because the deletion made the intron
too small for spliceosome assembly using the
authentic splice sites. They also identified a
9-bp direct repeat within the intron, which
probably facilitated the intronic deletion by
promoting misalignment of sequence.
Characterization of the PKD1 gene had been
complicated by rearrangements on chromosome 16
resulting in homologous regions in 16p termed
the homologous gene (HG) area (Hughes
et al., 1995). All but 3.5 kb at the 3-prime
end of the PKD1 transcript (which is
approximately 14 kb in total) is encoded by a
region reiterated several times in the HG area.
The HG region encodes 3 large transcripts of 21
kb (HG-A), 17 kb (HG-B), and 8.5 kb (HG-C), and
although these have 3-prime ends that differ
from PKD1, they share substantial homology to
the PKD1 transcript over most of their length.
It is not known, however, whether the HG
transcripts produce functional proteins. To
overcome cloning problems caused by the HG
region, Hughes et al.
(1995) isolated the full PKD1 gene using an
exon-linking strategy. They took RNA from a cell
line containing PKD1 but not the duplicate HG
loci and cloned a cDNA contig of the entire PKD1
transcript. The transcript consisted of 14,148
bp distributed among 46 exons spanning 52 kb.
The predicted PKD1 protein, called polycystin,
is a glycoprotein with multiple transmembrane
domains and a cytoplasmic C-tail. The N-terminal
extracellular region of over 2,500 amino acids
contains leucine-rich repeats, a C-type lectin,
16 immunoglobulin-like repeats, and 4 type III
fibronectin-related domains. The findings
indicated that polycystin is an integral
membrane protein involved in cell-cell/matrix
interactions.
In a study of PKD1 mRNA with an RNAase
protection assay, Ward et
al. (1996) found widespread expression in
adult tissue, with high levels in brain and
moderate signal in kidney. Expression of the
PKD1 protein, polycystin, was assessed in
kidney, using monoclonal antibodies to a
recombinant protein containing the C terminus of
the molecule. In fetal and adult kidney,
staining was restricted to epithelial cells.
Expression in the developing nephron was most
prominent in mature tubules, with lesser
staining in Bowman capsule and the proximal
ureteric bud. In later fetal and adult kidney,
strong staining persisted in cortical tubules
with moderate staining detected in the loops of
Henle and collecting ducts. The authors
suggested that the major role of polycystin is
in the maintenance of renal epithelial
differentiation and organization from early
fetal life. Polycystin expression, monitored at
the mRNA level and by immunohistochemistry,
appeared higher in cystic epithelia, indicating
that the disease does not result from complete
loss of the protein.
Qian et al. (1996)
developed a novel method for isolating renal
cystic epithelia from single cysts and showed
that individual renal cysts in PKD1 are
monoclonal. Loss of heterozygosity (LOH) was
discovered within a subset of cysts for 2
closely linked polymorphic markers located
within the PKD1 gene. Genetic analysis revealed
that it was the normal haplotype that was lost.
The findings provided a molecular explanation
for the focal nature of cyst formation and a
probable mechanism whereby mutations cause
disease. The high rate at which 'second hits'
must occur to account for the large number of
cysts observed suggested to Qian
et al. (1996) that unique structural
features of the PKD1 gene may be responsible for
its mutability. (This is a remarkable example of
the Knudson 2-hit mechanism, which has been
established in a considerable number of
neoplasms whose causation is based on
inactivation of both copies of a
tumor-suppressor gene.) They previously reported
an extremely unusual 2.5-kb polypyrimidine tract
within intron 21 of the PKD1 gene that they
postulated as being responsible for the gene's
increased rate of mutation (Burn
et al., 1995). Qian
et al. (1996) postulated that the
polypyrimidine tract may cause ongoing errors in
its transcription-coupled repair, thus resulting
in a high frequency of somatic mutation. Thus,
they concluded that PKD1 is a recessive disorder
when viewed at the level of the individual renal
lesions.
Brasier and Henske
(1997) likewise found evidence of clonal
chromosomal abnormalities in some renal cyst
epithelial cells with loss of the wildtype copy
of PKD1. Twenty nine cysts from 4 patients were
studied using microsatellite markers from the
16p13 region and looking for LOH. This supported
a loss-of-function model for autosomal dominant
PKD, with a germline mutation inactivating one
copy of PKD1 and somatic mutation or deletion
inactivating the remaining wildtype copy.
PATHOGENESIS
- Chapman et al.
(1990) reported that the
renin-angiotensin-aldosterone system is
stimulated significantly more in hypertensive
patients with polycystic kidney disease than in
comparable patients with essential hypertension.
They interpreted this as indicating that
increased renin release, perhaps due to renal
ischemia caused by cyst expansion, probably
contributes to the early development of
hypertension in polycystic kidney disease.
Wilson et al.
(1991) found evidence of reversed polarity
of sodium-potassium-ATPase in renal tubule cells
lining the cysts in this disorder.
Immunostaining with antibodies directed against
the catalytic alpha-subunit (182310)
was confined to apical, luminal plasma membranes
of PKD epithelia, a complete reversal of the
normal renal tubule polarized location in
basolateral membranes. Mislocated
sodium-potassium-ATPase was shown to be
functionally active, because identical intense
apical staining was observed by use of a
cytochemical assay. There was also an overall
6-fold stimulation of specific activity of the
ATPase in the cystic areas of early-stage APKD
kidneys.
Ye and Grantham
(1993) studied in vitro intact cysts that
were excised from kidneys removed from patients
with end-stage polycystic kidney disease. They
demonstrated that the cysts can secrete fluid,
and that net fluid secretion can be increased by
an unidentified secretagogue in cyst fluid.
These results suggested that the process of cyst
enlargement may be susceptible to pharmacologic
intervention. Normal and polycystic human kidney
cells can be cultured as monolayers in vitro.
Woo et al. (1994)
reported that, when placed in a stationary
suspension culture system free from the
influences of glomerular filtration, renal
tubular obstruction, and uremia, epithelial
cells from human and mouse polycystic kidneys
spontaneously develop into cysts in a process
that superficially resembles the formation of
the blastocele cavity. The ability of primary
cells from polycystic kidneys to form cysts in
vitro indicates that they possess intrinsic
morphogenetic information that is absent in
normal kidney cells. Inhibitors of DNA, RNA, and
protein synthesis did not prevent in vitro cyst
formation, but it was reversibly inhibited by
ouabain, amiloride, and the microtubule-specific
agents colchicine, vinblastine, and taxol. As
discussed elsewhere (263200),
cpk mice is a well-characterized recessive
polycystic kidney disease model. Woo
et al. (1994) found that the cpk/cpk mouse
developed PKD and died from uremia by 4-5 weeks
of age, but when treated weekly with taxol they
survived for more than 200 days with minimal
loss of renal function, showed limited
collecting-duct cyst enlargement, and obtained
adult size. The results were interpreted as
indicating that the microtubule cytoskeleton has
a central role in the pathogenesis of PKD in cpk
mice and that taxol may be useful also in
treating human polycystic kidney disease.
Woo et al. (1994)
considered it plausible that aberrations of
cellular functions mediated by microtubules may
lead to the apical mislocation of Na(+),
K(+)-ATPase, and epithelial growth factor
receptors in both human and murine PKD.
Hypothesizing that the progressive
deterioration of renal function in polycystic
kidney disease might result from a form of
programmed cell death (apoptosis), Woo
(1995) assayed apoptotic DNA fragmentation
in normal and polycystic kidneys biochemically
by gel electrophoresis and histochemically by in
situ end-labeling. A DNA-specific dye, Hoechst
33258, was used to detect morphologic apoptosis
in renal samples from patients with normal
kidneys, polycystic kidney disease, and other
kidney diseases. Apoptotic DNA fragmentation was
detected in polycystic kidneys from 5 patients
without renal failure and 11 patients with renal
failure but not in kidneys from 12 patients with
no renal disease. In situ end-labeling revealed
apoptotic cells in glomeruli, cyst walls, and in
both cystic and noncystic tubules of the
polycystic kidneys. No tubular apoptosis was
detected in renal-biopsy specimens from 5
patients with IgA nephropathy, 3 patients with
nephrosclerosis, 2 patients with focal
glomerulosclerosis, 1 patient with diabetic
nephropathy, 6 patients with acute tubular
necrosis, or 4 patients with acute and 4
patients with chronic renal-transplant
rejection. The capacity of polycystic kidney
cells to undergo apoptosis was retained in vitro
in the absence of uremia, ischemia, and other
confounding pathologic conditions.
At a point when only 7 mutations in the PKD1
gene had been described, Peral
et al. (1996) reported a systematic screen
covering nearly 80% of the approximately 2.5 kb
of translated transcript that is encoded by a
single-copy DNA. They identified and
characterized 6 novel mutations that, together
with the previously described changes, amounted
to a detection rate of 10%-15% in the population
studied. Study of the PKD1 mutation search in
the PKD1 gene is complicated by the fact that
most of the gene lies in a genomic region
reiterated several times elsewhere on chromosome
16. The results of the study of Peral
et al. (1996) had important implications for
genetic diagnosis of PKD1 because they indicated
that most of the mutations lie within the
duplicated area that is difficult to study.
Peral et al. (1996)
provided a diagram of the structure of the
polycystin protein with an indication of the
site of the mutations described to date.
Comparison of the phenotypes of patients with
large frameshifting or terminating changes and
those with more subtle in-frame changes showed
no obvious differences, suggesting that they may
all be inactivating changes. They cited evidence
of an alternatively spliced form of PKD1 that
contains an additional exon in intron 16.
Inclusion of this exon would change the reading
frame and result in the production of a much
smaller protein product. Hence they suggested
that all PKD1 mutations may be inactivating, but
those in typical families disrupt just the
full-length polycystin, whereas those associated
with large deletions disrupt both forms of the
PKD1 protein, resulting in a more severe,
early-onset disease.
Peral et al.
(1996) described a tyr3818-to-ter mutation
in the PKD1 gene in a severely affected child.
They found the same mutation in her clinically
normal twin brother and in her father who had
typical adult-onset disease. Because the same
stable mutation was associated with very
different disease severity in this family,
Peral et al. (1996)
proposed that a small number of modifying
factors may radically affect the course of type
1 polycystic kidney disease.
-
DIAGNOSIS
-
-
By Ultrasound
Begleiter et al.
(1977) noted that ultrasound is a valuable
addition to our armamentarium for study of
cystic kidney families. Sahney
et al. (1982) suggested that when an adult
with end-stage renal disease due to polycystic
kidneys is encountered without previous genetic
counseling (as was usually the case in their
experience), any children over 16 years of age
should have intravenous pyelography with
nephrotomography; those with negative studies
should be tested periodically with
ultrasonography until age 25 years. Diagnosis by
ultrasonography not only in adults but also in
the fetus was demonstrated by Zerres
et al. (1982). Sahney
et al. (1983) recommended ultrasonography as
the initial screening method in asymptomatic
relatives, followed by intravenous pyelography
if the sonogram is abnormal but not diagnostic.
Sedman et al.
(1987) performed ultrasonography or
excretory urography in 154 children aged 18
years or younger from 83 families with APKD.
They concluded that those children diagnosed
under 1 year of age may have a deterioration of
renal function early in life; however, those
identified in childhood by screening may have a
benign early course. In their opinion, the
finding of a single renal cyst in a child in an
APKD family should be considered suggestive of
the disease. Further, with history, physical
examination, and ultrasonography, APKD may be
identifiable in as many as two-thirds of
affected subjects during childhood.
From a study of 371 at-risk persons in 17
kindreds in Newfoundland, Bear
et al. (1984) estimated the probability of
clinical diagnosis of APKD to be 0.011 by age
20, 0.041 by age 30, 0.115 by age 40, 0.299 by
age 50, and 0.404 by age 60 years (expected =
0.50). Ultrasonography of 172 asymptomatic
at-risk persons showed definite APKD in 60. The
probability of ultrasonographic detection of
asymptomatic APKD was estimated as 0.222, 0.657,
and 0.855 at ages 5, 15, and 25 years,
respectively. On the basis of further analyses,
Bear et al. (1992)
stated that in 2 families in which the disorder
was not coinherited with chromosome 16 markers,
only 11% of members aged less than 30 years had
kidney cysts and the mean age of onset of
end-stage renal disease was later (68.7 years)
than for persons with the chromosome 16 form of
the disease (56.3 years). In PKD1 families, the
age of onset of ESRD was unrelated to the sex of
the affected person but was earlier in persons
inheriting the disease from their mother than in
those inheriting it from the father: 50.5 versus
64.8 years (P = 0.004). In PKD1 families,
resemblance in age of onset of ESRD was less
within than between families, and risk of false
negative ultrasonographic diagnosis appeared to
be restricted largely to families in which ESRD
occurred relatively late.
Dobin et al.
(1993) reported the results of classic
segregation analysis on 159 families with PKD.
They found that penetrance at the early ages of
onset had increased during the previous decade,
presumably because of improvements in renal
imaging and consequent earlier age of diagnosis.
In their study, the mean age of diagnosis was
estimated to be 20 years, with a standard
deviation of 15.94. Over 70% penetrance was
estimated by age 30 years, over 95% by 50 years,
and 99% by 55 years. The segregation ratio was
not significantly different from 0.50, but its
confidence limits were broad: 0.36 to 0.64.
Neither transmission probability nor penetrance
was significantly influenced by gender. The
mutation was estimated to be 6.9 x 10(-5),
consistent with the previously observed high
mutation rate for PKD. Dobin
et al. (1993) suspected, however, that the
mutation rate was overestimated in their study
because it neglected low penetrance alleles and
phenocopies.
Ravine et al.
(1994) used DNA linkage among subjects from
128 sibships within 18 PKD1 families to assess
ultrasound sensitivity. Currently used criteria
(bilateral cysts with at least 2 in one kidney)
provided good sensitivity (88.5% at age 15-29
years and 100% at 30 years and above), but
performance could be improved by less stringent
criteria in subjects aged 15-29 years and more
stringent criteria in older family members in
whom simple renal cysts are frequent. The
presence of at least 2 renal cysts (unilateral
or bilateral) in individuals at risk and younger
than 30 years may be regarded as sufficient to
establish a diagnosis; among those aged 30-59
years, the presence of at least 2 cysts in each
kidney may be required, and among those aged 60
years and above, at least 4 cysts in each kidney
should be required.
By Linkage
Trent and Wallace
(1989) and Vinet et
al. (1989) demonstrated that the presence of
deletion type alpha(+)-thalassemia is a
potential source of error in DNA linkage studies
for PKD1. The Caucasian family studied by
Vinet et al. (1989)
had the leftward type of deletion
alpha(+)-thalassemia which, except for 1 case in
a Mediterranean population (Troungos
et al., 1984), had been described only in
Asiatic populations (Winichagoon
et al., 1984).
Hannig et al.
(1991) reported on experiences with
presymptomatic testing for APKD by DNA linkage
analysis on potential renal donors among
relatives of patients. They emphasized that
thorough counseling before DNA analysis
(including discussion of accuracy and possible
testing outcomes of presymptomatic diagnosis of
APKD, diagnosis of noncarrier status, false
paternity, and noninformative study) was
essential for informed consent and to preserve
confidentiality within the family.
Confidentiality of potential donors found
presymptomatically to be affected (with a 94% or
greater probability) was especially difficult to
maintain. Since the use of living, related
donors for renal transplants provides
significant advantages over cadaver donors,
Hannig et al. (1992)
focused on the fact that presymptomatic testing
to determine the PKD status of potential donors
is an important consideration and DNA linkage
analysis is potentially more accurate than renal
ultrasound for prospective donors less than 30
years of age. Hannig et
al. (1992) found that of 5,026 renal
transplants done in 1988, 390 (7.8%) involved a
PKD1 recipient. Only 7% of these 390 transplants
used a living, related donor compared to the 20%
rate reported for all renal transplants. DNA
linkage studies were not used by any of the
centers surveyed and only 29% reported provision
of risk counseling. Hannig
et al. (1992) suggested that this
represented an unfortunate failure to take full
advantage of DNA testing. In 13 large Spanish
families, Coto et al.
(1992) found that all subjects over the age
of 30 who were shown by linkage to carry the
mutation had renal cysts by ultrasonography,
whereas 40% of carriers of the mutation younger
than 30 did not have renal cysts.
Prenatal Diagnosis
Breuning et al.
(1990) recommended that prenatal diagnosis
of PKD by chorionic villus sampling should be
attempted only after the linkage phase of the
DNA markers has been established by haplotyping
the index family. Furthermore, the families
should be of sufficient size to rule out the
rare form of PKD not caused by a mutation on
16p.
A survey by Hodgkinson
et al. (1990) seemed to indicate that there
would be little demand for prenatal diagnosis of
this disorder on the basis of linkage or any
other method.
Although APKD is typically a late-onset
disorder, ultrasonography has permitted the
detection of the disorder in the newborn or
infant in some instances and occasionally even
prenatally (Pretorius et
al., 1987; Ceccherini
et al., 1989). Turco
et al. (1993) described a case of bilateral
microcystic kidneys being detected by fetal
ultrasonography at 20 weeks' gestation.
Polycystic kidneys were demonstrated at birth.
The mother and at least 14 other members of the
family had typical APKD. In addition to the
renal involvement, the newborn had complex
skeletal manifestations including bilateral
complete syndactyly of the hands and feet,
bilateral polydactyly of the feet, and bilateral
agenesis of the tibia. Molecular studies
indicated that the infant had inherited the
disease-bearing chromosome 16 haplotype from his
mother.
-
CLINICAL
MANAGEMENT
- Pirson (1996)
reviewed recent advances in the clinical
management of autosomal dominant polycystic
kidney disease. He pointed out that, as in other
kidney diseases in adults, males reach end stage
renal failure (ESRF) 5 to 6 years earlier than
females. A deleterious role of hypertension was
suggested by Geberth et
al. (1995), who showed that the renal
prognosis of ADPKD was worse in individuals born
to an unaffected parent with essential
hypertension than in those born to a
normotensive unaffected parent. By contrast,
intervention studies failed to demonstrate a
beneficial effect of reduction of blood pressure
on the 3-year progression of renal failure in
patients with creatinine clearance between 13
and 60 ml/min. This does not mean, however, that
earlier intervention and a longer follow-up
would not have altered progression. Pirson
(1996) recommended screening ADPKD patients
aged 18 to 40 either by magnetic resonance
angiography or spiral CT for intracranial
aneurysm (ICA) if there was a family history of
ICA.
-
POPULATION
GENETICS
- Dalgaard (1957)
published a comprehensive landmark study in
Denmark which showed that autosomal dominant PKD
is one of the most common genetic diseases in
humans (approximately 1 in 1,000 individuals
affected).
In Wales, Davies et
al. (1991) estimated an apparent prevalence
of ADPKD of 1 in 2,459 in the general
population, an estimate that included predicted
affected family members. Higashihara
et al. (1998) estimated the prevalence to be
1 in 4,033 based solely on hospital admissions
and with no inclusion of family members. They
suggested that the fact that these frequencies
were lower than those based on autopsy studies
indicated that a considerable number of ADPKD
patients were asymptomatic or not sufficiently
symptomatic to seek medical attention.
-
ANIMAL
MODEL
- Himmelbauer et al. (1991,
1992) mapped 2 human
cDNA clones, derived from the region between
markers flanking PKD1, in the mouse genome. From
the study of recombinant inbred strains and of
somatic cell hybrids, they found that the PKD1
region markers mapped to mouse chromosome
17.
-
SEE ALSO
- Boichis et al.
(1973) ; Breuning et
al. (1990) ; De Bono
and Evans (1977) ; Dyer
et al. (1982) ; Gardner
(1976) ; Hogewind et
al. (1980) ; Kaye and
Lewy (1974) ; Milutinovic
et al. (1980) ; Osathanondh
and Potter (1964) ; Sanfilippo
et al. (1983) ; Stickler
and Kelalis (1975) ; Tazelaar
et al. (1984) ; Turco
et al. (1995) ; Wakabayashi
et al. (1983) ; Wolf
et al. (1978) ; Zerres
et al. (1985)
REFERENCES
- 1. Bear, J. C.;
McManamon, P.; Morgan, J.; Payne, R. H.; Lewis,
H.; Gault, M. H.; Churchill, D. N. :
- Age at clinical onset and at
ultrasonographic detection of adult polycystic
kidney disease: data for genetic
counselling. Am. J. Med.
Genet. 18: 45-53, 1984.
PubMed ID : 6741995
- 2. Bear, J. C.;
Parfrey, P. S.; Morgan, J. M.; Martin, C. J.;
Cramer, B. C. :
- Autosomal dominant polycystic kidney
disease: new information for genetic
counselling. Am. J. Med.
Genet. 43: 548-553, 1992.
PubMed ID : 1605247
- 3. Begleiter, M. L.;
Smith, T. H.; Harris, D. J. :
- Ultrasound for genetic counselling
in polycystic kidney disease. (Letter)
Lancet II: 1073-1074, 1977.
PubMed ID : 72973
- 4. Boichis, H.;
Passwell, J.; David, R.; Miller, H. :
- Congenital hepatic fibrosis and
nephronophthisis: a family study.
Quart. J. Med. 42: 221-233, 1973.
- 5. Brasier, J. L.;
Henske, E. P. :
- Loss of polycystic kidney disease
(PKD1) region of chromosome 16p13 in renal cyst
cells supports a loss-of-function model for cyst
pathogenesis. J. Clin. Invest.
99: 194-199, 1997.
PubMed ID : 9005987
- 6. Breuning, M. H.;
Snijdewint, F. G. M.; Brunner, H.; Verwest, A.;
Ijdo, J. W.; Saris, J. J.; Dauwerse, J. G.;
Blonden, L.; Keith, T.; Callen, D. F.; Hyland,
V. J.; Xiao, G. H.; Scherer, G.; Higgs, D. R.;
Harris, P.; Bachner, L.; Reeders, S. T.;
Germino, G.; Pearson, P. L.; van Ommen, G. J. B.
:
- Map of 16 polymorphic loci on the
short arm of chromosome 16 close to the
polycystic kidney disease gene (PKD1).
J. Med. Genet. 27: 603-613, 1990.
PubMed ID : 1978860
- 7. Breuning, M. H.;
Snijdewint, F. G. M.; Dauwerse, J. G.; Saris, J.
J.; Bakker, E.; Pearson, P. L.; van Ommen, G. J.
B. :
- Two step procedure for early
diagnosis of polycystic kidney disease with
polymorphic DNA markers on both sides of the
gene. J. Med. Genet. 27:
614-617, 1990.
PubMed ID : 1978861
- 8. Burn, T. C.;
Connors, T. D.; Dackowski, W. R.; Petry L. R.;
Van Raay, T. J.; Millholland, J. M.; Venet, M.;
Miller, G.; Hakim, R. M.; Landes, G. M.;
Klinger, K. W.; Qian, F.; Onuchic, L. F.;
Watnick, T.; Germino, G. G.; Doggett, N. A.
:
- Analysis of the genomic sequence for
the autosomal dominant polycystic kidney disease
(PKD1) gene predicts the presence of a
leucine-rich repeat. Hum. Molec.
Genet. 4: 575-582, 1995.
PubMed ID : 7633406
- 9. Ceccherini, I.;
Lituania, M.; Cordone, M. S.; Perfumo, F.;
Gusmano, R.; Callea, F.; Archidiacono, N.;
Romeo, G. :
- Autosomal dominant polycystic kidney
disease: prenatal diagnosis by DNA analysis and
sonography at 14 weeks. Prenatal
Diag. 9: 751-758, 1989.
- 10. Chanmugam, D.;
Rasaretnam, R.; Karunaratne, K. E. S. :
- Hereditary spherocytosis and
polycystic disease of the kidneys in four
members of a family. Am. J. Hum.
Genet. 23: 66, 1971.
PubMed ID : 5581983
- 11. Chapman, A. B.;
Johnson, A.; Gabow, P. A.; Schrier, R. W. :
- The renin-angiotensin-aldosterone
system and autosomal dominant polycystic kidney
disease. New Eng. J. Med. 323:
1091-1096, 1990.
PubMed ID : 2215576
- 12. Chapman, A. B.;
Rubinstein, D.; Hughes, R.; Stears, J. C.;
Earnest, M. P.; Johnson, A. M.; Gabow, P. A.;
Kaehny, W. D. :
- Intracranial aneurysms in autosomal
dominant polycystic kidney disease.
New Eng. J. Med. 327: 916-920,
1992.
PubMed ID : 1513348
- 13. Chapman, J. R.;
Hilson, A. J. W. :
- Polycystic kidneys and abdominal
aortic aneurysms. (Letter)
Lancet I: 646-647, 1980.
PubMed ID : 6102642
- 14. Coto, E.;
Aguado, S.; Alvarez, J.; Menendez Diaz, M. J.;
Lopez-Larrea, C. :
- Genetic and clinical studies in
autosomal dominant polycystic kidney disease
type 1 (ADPKD1). J. Med.
Genet. 29: 243-246, 1992.
PubMed ID : 1583643
- 15. Dalgaard, O. Z.
:
- Bilateral polycystic disease of the
kidneys: a follow-up of two-hundred and
eighty-four patients and their
families. Copenhagen, Denmark: E.
Munksgaard (pub.) 1957.
- 16. Dalgaard, O. Z.
:
- Bilateral polycystic disease of the
kidneys.In: Strauss, M. B.; Welt, L. G.
:
- Diseases of the Kidney.
Boston, Mass.: Little, Brown and Co. (pub.)
1963. Pp. 907-910.
- 17. Davies, F.;
Coles, G. A.; Harper, P. S.; Williams, A. J.;
Evans, C.; Cochlin, D. :
- Polycystic kidney disease
re-evaluated: a population-based study.
Quart. J. Med. 79: 477-485, 1991.
- 18. De Bono, D. P.;
Evans, D. B. :
- The management of polycystic kidney
with special reference to dialysis and
transplantation. Quart. J.
Med. 46: 353-363, 1977.
- 19. Ditlefsen, E.
M. L.; Tonjum, A. M. :
- Intracranial aneurysms and
polycystic kidneys. Acta Med.
Scand. 168: 51-54, 1960.
- 20. Dobin, A.;
Kimberling, W. J.; Pettinger, W.; Bailey-Wilson,
J. E.; Shugart, Y. Y.; Gabow, P. :
- Segregation analysis of autosomal
dominant polycystic kidney disease.
Genet. Epidemiol. 10: 189-200,
1993.
PubMed ID : 8349100
- 21. Dyer, P. A.;
Watters, E. A.; Klouda, P. T.; Harris, R.;
Mallick, N. P. :
- Absence of linkage between adult
polycystic kidney disease and the major
histocompatibility system. Tissue
Antigens 20: 108-111, 1982.
PubMed ID : 6958086
- 22. Ellis, D. S.;
Putschar, W. G. J. :
- Persistent fatigue,
hepatosplenomegaly and portal
hypertension. New Eng. J. Med.
278: 899-904, 1968.
- 23. Emery, A. E.
H.; Oleesky, S.; Williams, R. T. :
- Myotonic dystrophy and polycystic
disease of the kidneys. J. Med.
Genet. 4: 26-28, 1967.
PubMed ID : 6034518
- 24. European
Polycystic Kidney Disease Consortium :
- The polycystic kidney disease 1 gene
encodes a 14 kb transcript and lies within a
duplicated region on chromosome 16.
Cell 77: 881-894, 1994.
PubMed ID : 8004675
- 25. Gabow, P. A.
:
- Autosomal dominant polycystic kidney
disease. New Eng. J. Med. 329:
332-342, 1993.
PubMed ID : 8321262
- 26. Gal, A.; Wirth,
B.; Kaariainen, H.; Lucotte, G.; Landais, P.;
Gillessen-Kaesbach, G.; Muller-Wiefel, D. E.;
Zerres, K. :
- Childhood manifestation of autosomal
dominant polycystic kidney disease: no evidence
for genetic heterogeneity. Clin.
Genet. 35: 13-19, 1989.
PubMed ID : 2924430
|
