risk for first-degree relatives. From such .... Orlando,. FL) and with a family history of nephrolithiasis. (at least one affected sibling) ... ultrasound or plain x-ray film.
The 1 a-Hydroxylase Locus Is Not Linked to Calcium Formation or Calciuric Phenotypes in French-Canadian PATRICK SCOTT, DENIS OUIMET, YANICK GERALD GUAY, BERNARD GAGNON, LUC ALAIN BONNARDEAUX Service
de N#{233}phrologie and
Quebec,
Abstract. creased and
Calcium
production.
The
role
sibs,
using
analyses.
Sibs
with
1 17) had higher
a verified
24-h
interval
vitamin sibs
The
passage
from
a combination
a kidney
origin.
relatives
the
and
(
and
(n
urinary
serum
l,25(OH),
shows
absence
calcium idiopathic
non-
factors
urinary factors
potassium
as well
intake
Ncphrol
recurrent and has
have
between
of an affected
clustering,
It is usually in the
may
loss
of
and
predispose
the
as increased
demonstrated
proband
prevalence.
prevalence (parent,
For
stone
profamilial
for male
siblings
a value
higher
4,
insulin-dependent insulin-dependent
of the sibling,
analyses oxaluria,
calciuria
Ca/cr
formcrs)
ratios.
This
I a-hydnoxyla.se traits there
with
study locus
associated
to
with
is coaggregation
of
(I Am
stone
formation.
be estimated
to vary
1998)
model
of inheritance
younger
(7), disease
offspring)
the
lifetime
by
than about
stone
formation
mental
and
in and
when the
from
inactivating
termed
genetic
CLC-5;
factors
arc
stone
served
formation.
in monogenic
Nyhan
syndrome
ferase
deficiency)
et al. based
proportion
of affected
one of two oldest
relative
contribution
of environ-
of the with
to play
hyperoxalunia
in a renal 10),
In
addition,
such
chloride
also
that
in common
formation
as cystinunia
(hypoxanthine-guaninc
and
chan-
indicates role
stone
of
(8)
nephnopathy
a significant
disorders
molecular
the formation
hypcrcalciunic 9 and
is
to calcium
as primary
mutations
little
predisposing
elucidation
X-linked
siblings
However,
(5).
associated
references likely
lower than A polygenic
by Resnick
The
such
but 15).
=
2.5 non-
proposed
disorders (a rare
resulting
the
factors.
and
is a higher
of genes
or about
disease
=2),
are unaffected
number
genetic
(As (As
in which
both
nephrolithiasis,
calcium
A
there
from
hypertension
mellitus mellitus
in sibships
of monogenic
Dent’s
essential
has been that
siblings
known
nd
(As) can than
diabetes diabetes
on the observation
calcium
with an instudies, one
A factors
passage,
be excluded,
and
In addition,
to
is affected
excretion of calinclude decreased
termed
could
trait
or to quantitative
factor
bases surveys
locus.
locus
stone
formation
9: 425-432,
reveal
VDDJ
at the
and
phenotypes
not
recurrent
of the putative
oxaluric
stone-
did
Quantitative
of linkage
hypcrcalciuria. and
in
episodes)
sibs
to 24-h
D levels,
and
in 28 sib-
and
that
linkage
vitamin
stone
and
fonmens).
for
formcrs
(3
VDDI
to the
stone
evidence
stone
analyses
affected
a Ad of 2.0 (single
(recurrent no
recurrent
multipoint
among
formation
with
3.25
and
and
shared
of stone
(Cal serum
of environmental
include increased 1 ,2). Dietary risk
of family
ratios
Montreal,
with recurrent-only
Two-point
respectively,
Soc
result
factors
in alleles
revealed
=
chromosome
population,
can
excess
on
consequences. and
sibs.
Linkage
of single
(65 sib pains)
forming
calciuric
analyzed
sib pains)
0.02),
=
with
for kidney stone formation (4-6) for first-degree relatives. From such the
TROUVE,
H#{244}pitalMaisonneuve-Rosemoni,
(146
a 9-centiMorgan
is a common
medical
of metabolic
indices
population
locus
ships
and
linkage
(P
compared from
were
pain
intake (3). Large epidemiologic
extracting
oxalunia
0.02)
stone
Recognized
calcium,
derive
passage
in of
and/or infection. Calcium stones constitute the type of nephrolithiasis and are thought to result
to stone formation cium and oxalate
can
urobithiasis
VDDJ
intolerable
function prevalent
aggregation creased risk
trait
Markers
the
economic
renal most
fluid,
quantitative
I to 5% of the Caucasian
with
genetic
(P
120).
=
rate-
was evaluated at beast a pair
0.03),
=
la-hydroxylase)
of
associated
tein
D levels
affecting
important
(P
D
the
loading urine calcium/creatininc and P = 0.002, respectively), and
(ii
(putative
disorder
calcium
calciunia
encompassing
l2ql3-14
Guv-Bernier,
14 sibships
vitamin
I a-hydroxybasc,
and
in-
of calcium,
increased
vitamin D production, 28 sibships with qualitative
with
excretion
from
of the enzyme
fasting and postcalciuru en) ratios (P = 0.008 l,25(OH), stone-forming
associated
urine
to result
in active including
affected
often
and
suggested
limiting step 36 families,
is
absorption
been
de Recherche
PROULX, MARIE-LUCIE VALIQUETFE, and
Canada.
urolithiasis
intestinal has
Centre
Stone Families
(11
is ob),
Lcsch-
phosphonibosyltrans-
( 1 2), and adeninc
phosphonibosyltransferasc
Received July 9, 1997. Accepted September 22, 1997. deficiency ( I 3). Correspondence to Dr. Alain Bonnardeaux, Centre de Recherche Guy Bernier. Numerous studies have attempted to define the causes of H#{244}pital Maisonneuve-Roseniont, 5415 boul l’Assomption, Montr#{233}al, Qu#{233}bec, calcium stone formation by analyzing in vito and in vitro Canada HIT 2M4. biochemical markers related to calcium and oxalate ructaboI 046-6673/0903-0425$03.(X)/() bisru, and to inhibition of crystallization. Perhaps the most Journal of the American Society of Nephrology Copyright
U 1998 by the American
Society
of Nephrobogy
consistently
reported
anomaly
is
increased
urinary
calcium
426
Journal
excretion
of the American
(>0.
known
1 ruruollkg
per
cause,
i.e.
systemic
present
in approximately
only
5%
with
increased
in
the
Society
24 h). Hypercalciuria
population,
intestinal
that
idiopathic intestinal
(beading leak
idiopathic but rather
hypcrcalciunia the extremes by
hypercalciuric and
hyperabsonption,
hypercalciunia).
suggested
renal
with
However,
the
fact
that
are
various
now
deemed
degrees
event(s)
responsible
D pathway, intestinal explain
which
calcium this trait.
tribute
for
idiopathic
is the
only
hypencalciunia
hypercalciuria,
known
the
hormonal
and hence
D3 is the rate-limiting
vitamin
D3
(l,25(OH),D3).
percalciuria
maintain
similar
to
increased
urinary
percalciuric l,25(OH)2D3 infusion
given
of tnitium-labeled
changes inhibitor intestinal
calcium
is very
l,25(OH),D3,
absorption
and
subjects
renal
excretion
was
status.
and
an in
admin-
leukocytunia,
single,
and
urinary
Calcium
and
1 wk before
written)
to avoid
dairy
hydroxylase
locus
stone
formation
cium
metabolism
Materials Family
and
vitamin
putative
1 2q is not linked
or to intermediate and
the
phenotypes
to calcium
relevant
to cab-
D homeostasis.
the
first
Methods
informed
by institutional consent.
Probands
review with
comat least
ending
test was
two
Lunch gave
(i.e.
diarrhea, or small
Urine
elemental breakfast
glasses
(300
was delayed
yogurt,
samples
biochemical
were analyses
ml)
were
were
(verbal
and cheese)
and for 5 d
in 4-L disposable were instructed
verbally, a void, until
to initiate and
the
collect
the next
the morn-
void).
student
members
nurse
with
responsible urine
according
were
ascertained
a nephrologist
for the project
collection.
of water
were
calcium
protocol:
a 2-h
followed of 1 g of
Montreal, Quebec, Canablack coffee) was allowed, given
urine
to our institution performed
(Dr.
(P. Scott)
A supervised
to the following
after the final
transported
a
calcium
as diuretics,
defecation)
calcium (Novartis, (two pieces of toast,
until
hyper-
entailed
instructed
and
research
the 24-h
a
resection
restricted
as well
All family
performed
with (fever,
bowel
protocol
following
morning
radiologic Siblings primary
were collected Family members
during
ultrasound (renal colic,
status.
were
milk,
no
noted.
of infection
disease,
in writing
Test.
the trait.
a moderately
,
when
were
fasting urine collection (from 7 am. to 9 a.ru.) was obtained, by a 4-h collection (9 am. to 1 p.m.) after the ingestion
and
This study was approved
and all subjects
loading
Loading
effervescent da). A light
Ascertainment
Pedigrees. mittccs,
on chromosome
that
de-
resolution).
status
chronic
Patients
voided
on the morning
suggest
patient’s
from unaffected possible, to con-
evidence
supplements,
nurse,
1a-
results
(ra-
of pasthe total
no concomitant
phenotyping
immediately
urine
records when
for
under
products
or a Ph.D.
Our
to the
affection
The
sampling.
Bonnardeaux)
members.
bowel
vitamin
research
(including
stone
pyelogram
symptoms
but
culture),
collection
at 7 am.,
Calcium
definite
the unaffected
clinical
before the collection. Urine samples collection bags containing thymol.
ing
and
records
assessments
one
spontaneous
suggestive
an undetermined
24-h
(including
with
the hospital and x-rays),
with
Collection.
stopped
urine
sibs
the
clinical
according colic
of stone)
urine
assigned
by a clinical
for
of all
of a stone on an abdominal with suggestive symptoms
inflammatory
Urine
height,
passage
intravenous
as unknown
passage positive
also
24-h
weight,
symptoms when absence episode could be verified,
renal
no passage
af-
multiple
passage,
and/or
considered
large fected
that
participating
at least
We assigned
of stone
of stone
diet.
I a-hydroxylase formation, renal
with
After
analysis was performed on all stones available from biochemical analyses of stones from hospital records
and
by a clinical
descent
urology
we noted
sex,
where
determined and
concomitantly
of French-Canadian
or 36
relative
review
had
stone
calcium excretion, intestinal calcium absorption, and plasma 1,25(OH)2D3 bevels, we performed genetic linkage studies in families
records,
of stone
hospitals siblings
passage
were
collection
at the stone
at several
Age,
age
with suggestive If at least one
passage
were
(27).
To test whether genetic variation locus might be associated with calcium
respective
an unaffected
previous
Hy-
without
when
one and
city regions.
in each
a detailed
were retrieved. We also reviewed siblings (abdominal ultrasounds
parathyroidism,
(26). (4) Ketoconazole, induces a reduction
onset
by either
(stone
and
levels of Moreover,
increased
hospital
obtained
by
affected
of episodes
history a
(3)
and
the
verified
evidence
by the equilibrium are
recruited
and Quebec
Stones.
were
confirmed All
hematuria,
much
showing
( 19-22).
as measured
1 ,25(OH),D3,
to hypcrcalciuric
made.
episode
Renal
Episodes
from
were
for
Unaffected sibs with evidence or plain x-ray film and sibs
hy-
of calcium
excretion
in metabolic clearance rates of b,25(OH),D3 synthesis,
the
of active
that
probands
reviewing
pressure
were
available
firm
of calcium
idiopathic
absorption
calcium
rates,
study.
probands
Crystallographic the siblings,
to con-
may have increased plasma a free diet (17,23-25).
production
in the
blood
vitamin
hypothesis that could
with
balance
intestinal
fasting
subjects under
1,25(OH),D3
istered
subjects
of increased
sitting
scniption
for
in the formation
Subjects
a calcium
control
combination
step (2)
as
& Co.,
Traits
primary
stimulus
to the formation
from and
Status
dio-opaque stone) sage, or surgery.
and
stones, a disordered 1a-hydroxylasc activity is perhaps most attractive for the following reasons. (1) 1 a-Hydroxylation of vitamin
and
number
absorption, is a preeminent Among the candidate genes
to hypercalciuria,
of (18)
the
content Herring
and unaffected siblings and parents, parents were deceased. We ascertained
in the Montreal
interviews
Affection
of
proportion
regarding
C.
a family history of nephrolithiasis (at least interviewed by a clinical research nurse
clinics
Phenotvpic
D
“unclassifiable”
of fasting
intestinal calcium hyperabsorption. Although controversy persists
(Louis
26 of 36 families (28 sibships) comprised at least one pair of affected siblings with one or more verified episodes of nephrolithiasis.
beak
categories
a significant
calcium-oxalate
analysis
sibships
conducting
phos-
vitamin
these
of predominant
idio-
renal
increased
FL) and with sibling) were
French-Canadian
from
calcium
and
stone
crystallographic
and nephrobogy
might not represent specific entities of a continuous spectrum ( 17). This is
subjects
present
and results
to hypophosphatemia,
and
and this
of calcium,
of renal by
asked to contact affected intervening relatives when
reports
using standard seg(16) have proposed
excess
episode
Orlando, affected
associated
is heritable (14, 15), but
hypenparathyroidisru),
(leading
production,
also
calcium
dietary
one
determined
with
Sporadic
is heterogeneous
including
to secondary
phate
is usually
hypercalciunia dominant trait
hypercalciunia
of causes,
compared
absorption.
has not been rigorously tested analysis. Further investigations
a variety pathic
formcrs and
calcium
a is
without
hypercalciuria,
of stone
have suggested that idiopathic transmitted as an autosomal hypothesis negation
idiopathic
,
40%
general
of Nephrology
on the
at 9 am.
and
was collected on the same following
day.
I 1 am.
(I p.m.). day,
and
1a-Hydroxylase
Biochemical samples
Analyses.
was
determined
MO).
Biochemical
performed by
Serum
an
enzymatic
assay
l,25(OH),D3
Stillwater,
MN).
control
test
levels.
Serum
using
an RIA
levels
Interassay
sample
analysis
by an autoanalyzer.
and
intact
(Sigma
1 1.2%
Institute,
St.
was
with
levels
Juan
were
Capistrano,
three
Transmission
on
a
(+50%)
shown
assessed
genes
to be a powerful
heterozygous
CA).
Genotvping lymphoblastoid
from
cell
in linkage
lines.
disequilibrium
chromosome
l2q (VDDJ and telorueric
(D12S368)
amplified
well plates town, MA) (yP32)
We
used
with
the
established
marker
(D12S90)
a polymorphic putative
1 a-hydroxylase
a 9-centiMorgan
the dinucleotide
or from
region.
from
DNA
in 96-
under
standard
conditions.
gel electrophoresis ethylenediamine from reading were assigned
increasing
by
PCR
products
were
(6% polyacrylamide, tetra-acetic acid). the major bands starting at I for
1 for each
step
for the
to
and
1X were
each subject. Allele shortest allele, and
of I dinucleotide
repeat.
times
correct
for
a Sun ULTRA programs (29) distances ratio
I work were used
on our
at least with
to data
published
pairs
most
the next
likely
best
order)
for
Genetic
with
was
parameter-free shared
compared
(33).
Missing
mation rental
methods.
all pairs
number
of independent
available
were
two-affection
the proportion
(version
2.1)
from
estimated
status
i.e. from
in pairs
founders
in the
for at least one episode
(version
2.2) of SAGE.
available methods
to estimate
onset
in six different
status were
(affected, performed
with
24-h
Cockcroft-Gault
unaffected, using the
of alleles
creatinine
program
We
based
by each
unknown). Quantitative linkage squared sib-pair trait difference
shared (32)
identical-by-descent. within were
calcium
loading
used.
20%
of that
Regressions
were
X or
out of (X +
tests one should
that
have and
at least
five
P values
ratio-based
were
transmission
jointly
and
offspring but not in the TDTLIKE when
male
as well
their
sizes.
available that
test,
and
shown
index,
allows
the other program
genetic
infor-
reconstruct
pa-
of coru-
intervening
deceased
rela-
A total
of 237
of them.
and
unaffected)
a
serum
biochemical
24-h
underwent
urine
collection,
analyses.
2. There
or weight
sibs (not
number
pedignees
342
(affected
in Table
as the
The
included
height,
on female
for
were
shown).
There
a
Clinical
no differences
in affected
difference in unaffcctedlaffectcd ratios male siblings (P < 0.001) in complete
Table
1. Number sibships
of calcium according
No. of Affected Siblings per Sibship
of
bike-
of age
of
affection analyses regressed
unaf-
versus
was a significant
between sibships.
male Three
and fesets of
by the performed
stone-forming to disease
families
and
status No.
Status
of Sibships
I”
Status
2’
1
24
2
13
6
3
6
6
4
2
1
5
3
0
6
3
0
7
0
0
8
1
1
10
Total
no. of sibships
52
24
Total
no. of families
36
20
Affected b Affected
individuals individuals
Urine collections predicted
parents
completed
by
transmitted
all alleles
(including
was
are mass
on the infor-
maximum
parent’s
analysis
alleles
pedigrees,
siblings
evaluation
of stone passage.
uses
individuals DNA
clinical
used
severity
of the distribution
determined
excretions
formula
This
parameters
classes,
469 and
of stone passage). An subroutine program
was included,
in the pedigrees.
pro-
are computed
us to unequivocally
and
1 . Allele
families. to the
the
sibships
tives),
to the
minus
according
they
Siblings
and
multi-
according
of sibs
which In this
under
to calculate
weighted
number
,
of siblings,
(sibs concordant
on the number
expected
were
allowed
of with
with
considered,
considers
offspring
(34).
A likelihood
that
in detecting
children
of necessary
only
test been
the frequency
of heterozygous
genotypes
I describes
prised
likelihood scores) and allele all of the pair data available,
a sibship,
pairs,
(31)
and sibs concordant for at least three episodes age-of-onset covariate computed with the
lihood
qualitative in affected
TDTLIKE
Results
fected
markers
For
and
frequency
under
were
testing.
parental
analysis
distribution
the number way,
in the pedigree haplotypes.
characteristics
is similar
between
identical-by-descent
with
program
we used
mation
D/2S368-D12S90-
linkage
offspring
test (TDT)
same-generation
a likelihood
2.3 cM. This
the
affected
of the allele
multiple
disequilibrium
in body
point Lod scores (MLS, or maximum sharing with all three markers. To extract
AGEON
on
of independent segregation of marker and trait, using program (ANALYZE package) and SIBPAL programs from the SAGE. package (30). We also used the
MAPMAKERISIBS
the disease
(with
was and
compiled
and CRIMAP calculate genetic
order
of6.7
Method. of alleles
of a sibship
frequencies
programs
The MULTIMAP the markers and
intervals
analyzed
number
the hypothesis the SIBPAIR (version 2.6)
using
by G#{233}n#{233}thon.
was
the
The
over
Sib-Pair
traits
station. to order
sex-averaged
Affected traits.
performed
pedigrces.
1000:1
D12S83,
and
were
with
to be transmitted
corresponding
analyses
root,
the
all affected
comparing
a binomial
in an unbiased
Sibships
Analyses
All genetic
from
To reduce
opportunities
allele,
to their
to affected
Table Linkage
used
to sib-pair
that one allele be transmitted to affected alleles was also performed, as implemented
submitted
7 M urea, and genotypes
P values
Y) opportunities.
corrected
We enzyruat-
genomic
square
We
and evaluates
allele
allele
at the probability
more on
as well as centromeric to D12S90 from the
(cM)
repeats
gene
this
other
exact
alternative for a given
transmit
the
looking
using a thermal cycler (PTC-bOO; M. I. Research, Waterin 30 cycles of PCR with one of two primers end-labeled
denaturing Tris-borate determined numbers
leukocytes
locus; reference 28), (D12S83) markers
G#{233}n#{233}thon map spanning ically
peripheral
Test.
disequilibrium parents
they
gram, extracted
(untransformed,
Disequilibrium
in gametic
transmit was
of measurement
427
program ofthe ANALYZE package as an intrafamilial association on multiplex as well as simplex pedigrees (33). This test has
which
DNA
scales
Nephrolithiasis
log-transformed).
Louis,
24.4%
increased
(PTH)
San
were
by RIA (INCSTAR,
coefficient
hormone
bevels
Diagnostics,
on a sample
parathyroid
under
and serum
oxalate
were measured
variation
kit (Nicholls
of urine
Urine
in Calcium
a
with at least one episode with at least three episodes
of stone of stone
passage. passage.
428
Journal
of the American
Society
C
C C
-
C
C C
---C
+
+
r
C
+
ri C C
C
(I C C
twins
analyses).
C.’
stones
Q;; +
+
C
.
II
C1
II
II C
00
C
0
C
00
II
and
r-
stones).
C
Of
00
ammonium
II
+1
+1 rq
d
single
in
those,
d
C C
with
+1
Relatives
00
undetermined
r1 C
00
II
ri
C
0
-
5) 0
0 C,)
C N
O
+1
+1
CO
--CCC
+1 +1
+1 +1
-Cr
+1
r1t
5)
p
“C
‘i
“z1:
Q
0
C
+1 -
f2
0
the
latter
two
affection
with
three
one
uric
types
inflammatory for
and of
status,
was
acid
two
disease
acid
were
assigned
an
other
siblings
(af-
and
hyperparathyroidism,
were
uric
ncphrolithiasis).
of stones
as were
bowel
(18
one
calciuru-oxalate),
history
intermediate Phenotype
Phenotypes characteristics
previous
para-
respectively.
in Siblings are also included
this
difference
was
were
also
significant
increases
.C)
r1
00
00
-g
significant differences weight between affected
creatinine
ratios
The
urinary
24-h
forming
in
in Table
24-h calciunia and unaffected
only
significant
in
in fasting
and
2. There
corrected siblings.
for How-
women.
There
net
(z)
cabciuml
in affected
compared
with
unaffected
siblings.
oxalate
excretion
was
increased
in stone-
siblings
+1
+1
+1
+1
+1
+1
N
1 ,25(OH),D3
5)5)
compared
with
were
slightly
lings.
. .-
and
0 C
C
U
C
ri
C
C
(
C
C
C
r
---C
+1 +1 +1 +1
5)
\C
N
00 -
.0
C,)
C
Cr
II
II
non-stone
formers.
5)
C
cq
II
D12S368,
I C
‘i
-;
0 -.E
.
C
C
V 0
r1
C
z1
+1
+1
C
‘C C-.. C#{149}
C,)
+1 r’ C
+1
+1
L5
C
=
U
.e
.c
C,)
V
U 0
0_
ea
C)
E
a
shared
at
C)’,’ 5)
-c5) “0E
U ci
V0
.0
U
C-)
ei
C+_C._
0
E
ci
5)5)
Li
U
“CC)
5)0
._,
-c
.
sci
C
between
not
Serum
affected
sib-
calcium,
stone-forming
and
shown).
CO >
of the
]ct-Hydroxylase
1 3 alleles,
sibs,
shows
D12S90
(data
not
shown).
(LOD
score, locus
for
and
spectively. was in
also
4,
transmission ing
the
the
No
linkage
was
pairs
were
considered
on no
absence
present of linkage
that
allelic
not
associated
and
The
and for
simplex
in this
subset
to the
for
the
the
single-and-
phenotypes,
ne-
ANALYZE
package As
locus. putative
shown in
of pedigrees,
at the
allele
confirm-
Therefore,
the
1 a-hydrox-
-‘
eiead”
U Li
“1
10
ci0
U
and
ever,
0
0
(27
stones
-
“0
U
for all
sibships
calcium-phosphate,
phosphate,
CO
C
C)
-
ci
available 14
0
0
U
Crystalbo-
calcium
four
ci) C)
C
r-
ci 0
twin
from
predominantly
were body
Lt
5)
.-0
were
a known
with
fected)
0
5)
23
magnesium
+1
0
r
‘.co -;-
three
.c
f C
\
than
was
siblings
kidney
the affected
pregnancy.
of stones
affected
in the
of
(more
with
during
calcium-oxabate,
thynoidectomy 00
stone
included
presence
formers
analysis
22
the
discordant,
calcium-phosphate
C ,,:
+1
r’1
a
stone
was
one twin
for
C
predominantly
C
+1
pair
or biochemical
(spouse
00
recurrent
graphic
and
(only
concordant
one
passed
probands
I’
C
were
having
C
00
phenotyped
were
and
mixed 5)
were
Two
episodes),
c1
-
identical
ri
c
:
of Nephrology
susceptibility
to
calcium
Ia-Hydroxylase
Table
3.
Sib-pair
linkage
severity
of disease
Type
analysis
of calcium
and/or
No.
of Pairs
Affected
(
affected-affected
Affected (3 episodes) not affected-affected
a
Expected
ratios
LC
Expected
shared:nonshared
are 0.25,
:
Measurement
0.50.
of departure
from
1 Allele
IBDh
to
SignificanceC
2 Alleles
Shared
Not
Shared
x
P
43.6
0.01
NS
21.1
46.1
22.8
105.8
108.8
0.15
NS
1 1 .9
22.0
1 2.8
56.9
55.9
0.03
NS
1 8.6
42. 1
26.5
108.8
97.4
2.93
NS
4.3
6.8
8.4
26.8
19.7
2.60
NS
0.25
for sharing
is 50:50.
IBD,
expected
Status:
2 alleles,
respectively.
by descent.
shared:nonshared
(TDT)
At Least
0, 1 , and
identify
50:50
test
Transmitted
VDDJ
of the
(x
ratio
with
(D12S90)
1 dO.
locus
in 36
1 Episode
kidney
Affection
Not Transmitted
TDTi
Status:
Transmitted
ph
stone
pedigrees At Least
3 Episodes
Not Transmitted
TDT”
ph
2.78
0.43
1
14
8
1.64
0.60
7
2
2
37
44
0.60
1.00
18
24
5
21
20
0.02
0.98
11
6
6
24
31
0.89
1.00
11
17
1.29
1.00
7
55
40
2.37
0.37
28
23
0.49
0.87
8
14
19
0.76
1.00
0.91
1.00
Estimates h Corrected
for alleles that appear for multiple testing.
a
Genetic Linkage Analysis to Vitamin D Levels and Given
the
copies,
possibility
which
appropriate VDDI
locus
ularly
justified
strate
several
unia.
We
because
intestinal
oxalate
nine
before
ratios
complete
in Table
quantitative
5,
traits
sib-pain
no
square marginally but when group
genotypes are available values were noted (not lack
and
of
linkage
stringent
and
(and
for under
to scales
the analyses not
the
D12S90
definitions),
to
were
to
vitamin
in these
D physiology
and
hypercalciunia
We
have
with
barriers.
(since
tages
an
elevated defined
factors,
as well
to
disease,
susceptibility
any
with
the Mul-
noted
pairs
homogeneity
of the
the
of
the
decreased
with
detect
at close
1 (VDDI)
skeletal
in
25(OH)D3,
strongly
markers), suggests
no significant that, in addition
1a-hydroxybase dysfunction
activity (likely its p450 component) of a regulatory protein (35). Proof that
the
discrete
traits
(with
to quantitative
defect assay
involves on
decidual
suggests
that
I a-hydroxylation cells
from
of 1 a(OH)D3,
it is secondary
has patients
been with
The
but
not
to
to decreased
obtained the
and
changes.
group
which
is
phosphate,
smaller
doses
(VDDJ
gene type
specific
to physiologic
major
proximity
on to the
response
advan-
contributing
to
calcium,
severe
the
pool
power
rickets
located linguistic
to environmental
1 a-hydroxylase
plasma
and
have
markers
D deficiency
levels,
and of
due
of
popula-
because
obigogenic
used
putative
pedigrees
recently,
variability
have
locus
with
l,25(OH),D3
genetic
increasing We
putative
until area
size
thus
Pseudovitamin
associated
rate
of the large
homogeneous
geographic and
as the
studies from
a genetically
reducing
boci.
the
locus).
linkage
birth
Geographic of potentially
the
genetic in sibling
descent,
a well
As demonof
locus
French-Canadian
serum
of measure-
conducted
carried
no linkage
is
sibships.
1 a-hydroxylase
within
to calcium
load.
linkage
relevant
tion
calciumlcreati-
root, and log-transformed). significant P values were
for all three shown). This of
on
and
three
demon-
oxaluria
coupled
calcium
to
hypercabci-
analyses
evidence
obtained
0.66
Discussion
the
is partic-
pedigrees
linkage
an oral
it is
at
This
calciunia collections,
6
1.00
1.47
pheno-
study,
relevant
idiopathic
is indirectly
after
was
ment (untransformed, tiple test-corrected, oxalunia,
24-h urine
and
our
variation
in our to
traits present
phenotypes
sibs
genetic absorption
on
genetic
related
and
Locus
include
of
hypercalciuria.
affected
performed
absorption)
for 24-h
idiopathic
levels
might power
intermediate
characteristics
l,25(OH),D3
strated
to
and
the
5
0.86
times.
1 a-Hydroxvlase Phenotypes
whether
is linked
five
sibships
decrease
determine
handling
at least
of the Calciuric that
would
to
calcium
the
Alleles
according
37.4
Transmission/disequilibrium
Allele
relaxed
of Parental
locus
(D12S90)
5.0
and
ratio
Affection
to
No.
VDDI
17.9
affected-affected
entire
Sharing”
at the
I episode)
affected-affected
4.
disease
9.9
Unaffected
Table
stone
429
Nephrolithiasis
of Analysis 0 Alleles
not
radio-opaque
in Calcium
disease
the
or to basic
by direct (36).
In
430
Journal
Table
the American
of
5. Genetic
link age
significance
Trait
Society
analys
values
of Nephrology
is of quantitative
on
-
scales
Slope
of the Recression
Anal
per
rebated
pen
urine
the specific
kidneys
from
0.66
0.70
0.80
0.83
0.68 0.88
0.66 0.87
0.66 0.79
d
+0.01 +0.07 I .39
0.06
0.05
0.04
-
of calcium;
UOxV,
urine
oxalate
excretion.
with
deficiency
has been
analogous
disorder
the
Squared trait difference on the alleles IBD
confirmed (37).
in These
linkage is possible only when the value matrix, corrected for multiple testing.
multiplex
sib-pair
gathered
thus
far.
at
and
this
to
tionab
families,
would
be required
yses
presumably
linking
an effect from
through
disease
and
a gain
idiopathic
to VDDI
D12S90
isolated
population
of
of function,
is linked
hypercalciuria.
have
been
French
The
performed,
Canadians
linkage,
but also
linkage
in part,
with
disequilibrium.
that the genetic distance between the likely to be in the infra-centiMorgan
susceptibility
locus
formation (at least stone
fonmers)
This and
D12S90
range
predisposes
affection
that
mediate cluding
this
status.
locus
intestinal
absorption
as 24-h
allelic
phenotypes. dered posed
to calcium
urine
variation This
a major
These
results
any
VDDI boci is (38) and that
and
using
gene kidney
as a stone
we have
not found
variance
of inter-
an oral adding
calcium further
is not associated
load), evidence
with because
production to explain
has been proidiopathic hyper-
contributing apply
to calcium to the
stone
families
a disor-
formation
studied
here,
study
traits
allows
stone
conduct
segregation (penetrance
traditional
parametric
related
formed
scnibed
for
[39],
the
,
it is well
that and
status
trait,
and of
I
Addi-
linkage
analysis
effects.
in all
However,
it has
not
been
our
pedignees
to
would
indicate
genetic
pa-
gene
frequency)
For
stone
such
red
to use
intermediate
formation,
using
the
blood
inferred
no
in
quantitative data
are
available
the
the (42)
We and/or
that
Second,
cofactor
and
other
we
it is also still
frequencies
do
apply
not
only
abbe
possible
some
notes
to the
D12S90
investigate
this
locus
scientific
in
at
the
encodes
of the enzyme,
be of significant
of
are present
to
that
component
and
families.
provide
1a-hydroxylases
are
not the P-450
have
a
although
interest
even
if
case.
also
and
shown
oxaluric
radio-opaque
primary
purpose
sidening
that
published, homogeneous
findings
and
analyses
be performed to conbe valuable in demon-
across
we
[40],
linkage
(gene
could also
results
results,
that
countertnansport
parametric
]),
a segreeffect is been de-
enzyme
parameters
present
it is possible
moment.
[4 1
of the
these
First,
kidney
that gene have
sodium-lithium I-converting
genetic
homogeneity
region;
In the event
phenotype bevels) findings. This would
In publishing caution.
cell
E levels
corresponding roborate our strating
information.
angiotensin
immunogbobubin
calciuric
because
parents
analyses.
serum
calcium handling in certain individuals, hypothetical mutations of this gene must stone-forming population.
design
both
for
genetic
is a late-onset
for to the
of 0%).
parametric weaken
disease
available
consistent with that of a major well known major gene effects
the
the
sib-pair
fraction
function
to provide
gation pattern obtained (e.g.
would
an affected
respectively,
alternatively,
stone
boci contributing
3.25,
to calcium
were
used
kidney
on the proportion of phenotypic variability that would result from genetic effects. Segregation analyses on quantitative traits in nuclear families, as well as twin studies, should be per-
study
have
and
is negative.
of pairs
of major
analyses
rameters
calcium
at a necorubination
passage
that
We
exclusion
to detect
to phenotype
this
suited to situations in which inheritance of the trait is complex on unknown. To our knowledge, this is the largest collection of
the number
or,
and although they do not completely rule out the possibility that genetic variation at the 1a-hydroxylase locus has major effects on kidney stone formation or on intestinal and/or renal they do indicate that be uncommon in our
with
Presently, (Ad of 2.0
episodes,
possible
traits
pedigrees the
considered
3
kidney
relevant
important,
1 ,25(OH),D3 hypothesis
obviously
of the
after
excretion,
is particularly
trait
when
to 1 a-hydroxylase activity, inlevels, urinary calcium excretion,
at this locus
regulation of as a preeminent
calciunia,
Moreover,
(24-h oxalate
suggests
sibships by using a relaxed a more stringent (recurrent
explains
phenotypes relevant serum 1 ,25(OH),D3
as well
(22).
that
in our group of multiplex one stone passage) and
evidence
that
on
a founder
maximal power is achieved for linkage analyses this marker. We have excluded the putative 1 a-hydroxybase
and
anal-
dated 12 generations ago, and all affected individuals the same region carried the same allele (28), indicating
not only
Log
0.78
this
stone
nominal
Root
Square
its to
locus,
with
on Scalec
Untransformed
results strongly indicate that 1 a-hydroxybasc or one of cofactors is the defective protein, and that markers linked VDDI can be analyzed to evaluate whether genetic variation calcium
locus
0.65
enzyme
pigs
to the D12S90
-0.002
excretion
addition,
formation
P Values
Values for slopes are shown for untransformed phenotypes. p values for regression analyses of the squared differences
h
C
stone
.
sis
y
to calcium
measurement”
d
Ca/cr
UOxV/kg
UCaV,
a
of
+33.5
b,25(OH),D3 UCaV/kg
Fasting Calcr
traits
three
the
that
kidney
of the a number
there
phenotypes
study of
is familial with
stones.
and studies
use of family-based study design than
the
coaggregation passage
Although
this
is an expected on
the
of
of calcium was
not
the
finding
con-
have
been
subject
controls provides simple case-control
a more analysis.
Ia-Hydroxylase
Affected
sibs,
excretion
of
previous tion. excretion
be
intestinal
frequent our
and
of
excretion
calcium
loading
prevalent
in women,
trend
toward
excretion. affected
ble ages.
findings
reflect
factors
variance
This
with
findings,
the
This
study
A
with
case-control
the
vitamin
study,
production (from
hypercalciunia
and/or
encoding proteins and the intestine, zation
D receptor
inhibition will
calcium
of urine
be particularly
would
(syntenic)
human
boci
genetic
hypercalciunic
under through
way (45). subsequent
should
provide
weights
tion
As
estimation
idiopathic
hypencalciunia.
structure
and these
of calcium
stone
linkage studies
approaches
formation
and
4. 5.
cDNA cloned M,
Added
Since
for 25-hydroxyvitamin in the mouse (Takeyama Yanagisawa
hydnoxylase
1997), been
in Proof:
identified approaches
and
respective
stone be
6.
Parks
JH, Coe
Semiti
Nep/irol
and published
J,
Kato
and
vitamin
the
human (Monkawa
5:
faru-
cDNA
and
T, Yoshida
genomic
for calcium
Omdahl
used
with
recent IL,
rickets
(PDDR) 1997).
This
as a major
formation.
DNA
Kidney
Foundation
Dr. Bonnardeaux
du Qu#{233}bec.We
and
the
is a scholar
of
thank
Dr.
Kenneth
the
9.
Plenum,
atic kidney McGeown
of calcium
stones.
5, Shinki
10.
also T,
M,
Robertson
P1: The
in man:
main
Hypercal-
198 1 , pp 3-12 W, Rimm E, Stampfer M: A prospective study and other nutrients and the risk of symptom-
Pridgen
W,
N:
328: 833-838, stone disease.
D, Goodman oxalate
Peacock
1993 Cli,z
Sci
19:
M, Baker
strategies Am
C, Purdue
Molecular by
M,
for
J Hum of
predisposition N Engi
Marshall
1995,
Wrong
genetically
Genet
to
J Med
278:
D, Pearlruan
222-228.
hyperoxalunia.
B,
A, Sly
W,
traits.
I.
1990
In: The Metabolic
Disease,
Vol. Valle
II,
7th
D, New
Ed., York,
pp 2385-2424 Fisher SE, Steinmeyer K, Schwappach B, Bolino A, Devoto M, Goodycr 0,
Ientsch
TI,
common molecular basis for three eases. Nature 379: 445-449, 1996 Bonnardeaux A, Lapointe JY, Bichet An unturned Gaspanini
complex
46:
Inherited
C, Beaudet
Lloyd SE, Pearce SHS, Scheinman SI, Harding
MI,
calculi.
A: Studies on the prevalence and disease in men in Leeds. Br J Urol
P: Primary
Bases
Scniver
SPA,
H: Genetic
renal
1983
Linkage models.
Danpure
Calonge
disease
In: Urolithiasis Clinical Basic Robertson WG, Finlayson B,
LH,
stones. N Engl J Med M: Heredity in renal
hypercalciuria: 1 1.
D, Heyburn
stone
1960
Resnick
Risch
treatment
M, Ouimet oxalate
mild hyperoxaluria? edited by Smith
York,
Rigden
balpha-
1827-1830,
have
and 1. 1996
Peacock
Curhan G, Willett of dietary calcium
and
has been T, Koboni D3
277:
T, Wakino
JM,
la-hydroxylase
by the
16: 398-41
WG,
factor
Multilocus 8.
defined.
manuscript,
25-hydroxyvitamin Science
that
D12S83
1552-1559,
stone
FL: Pathogenesis
Robertson
edited
D3 la-hydroxybase K, Kitanaka S. Sato
D synthesis.
human
and
Mom
12:
of Canada.
risk
55: 595-598,
7.
forma-
pathophysiology
this
the
D 1-abpha-hydroxylase
the
Speed R, Sergeant V. Smith epidemiology of urinary stone
hypercalciuria. submitting
site
determined
D-deficiency
supported
Council
McGraw-Hill,
Note
of
We
agreement
5,
kidney
formation of calcium 1313-1318, 1968
currently
are
to
were
465-471,
It
the optimal the
3.
excrc-
are
studies
ciuria or Research.
boci-
calcium
remain
elucidate
oxabate
Research
New
in
corresponding
oxabate
2.
D
candidates.
number
However,
should
ab-
1.
nor action Other
studies
to calcium
same
by the kidney on in crystalli-
to renal
of the
linked
of
is implicated
further candidate genes investigations, genome-wide
a first
lack
with
activity)
Such
calcium
tag
References
vitamin
at the
Medical
Combined
formation.
linked
map
in
Res
excluded
a
genes
the
(44).
be interesting
rat.
boci
Ultimately,
(on locus)
increased
to look
of genes
of genetic
and
ily
stone
important
tion
in the
locus
involved in calcium handling in the metabolism of oxabate,
have
on
Genet-
sequence
D12S90
> 15),
the Fonds de Recherche en Sante Morgan for helpful discussions.
linkage
a
expression)
we
the
1995).
Messerlian
Miner
gene
Research
STS-based
pseudovitaruin
J Bone
enzyruatically
Institute (Hudson TI, Stein Silva I, Slonim DK, Baptista
25-hydroxyvitamin
to the that
These at
nephrolithia-
1a-hydroxylase
vitamin
R,
Res
Acknowledgments
but
of candidate
neither
to
25-
Biophvs
of the
(BG4,
markers
score,
The
locus.
An
between
(Lod
FH:
for
panel
1945-1954,
(St-Arnaud
maps
gene
slightly
present
D12S90
study
confirms
compared
(23-25),
formation
that
increased
increased
receptor
stone
suggests
found
demonstrated
to the
and
this
(from
D
(43)
SH:
270:
we
3’ region
T: Mo-
human
on calciunic
calcium-oxabate study
centromenic
hypencalciunia
disease
is undetermined.
and
this
gene
the
results
in
menopause,
formers
of
is located
Gbonieux
stone
Xu
L,
gene
of comparakidney
respective
the
findings
urine
the
Science
Biochem
the
hybrid
gene
for
Therefore,
from
map of the Whitehead 5, Ma I, Castle AB,
Krugbyak
with
have
hypercalciuria
and
our
also
of these
a modest
locate
1997).
431
Sanuta
DNA
1abpha-hydroxylasc. tag
M,
genomic
radiation
genome.
were
studies
view
particularly
more
we
on the analysis
of
sonptivc
In
diet,
previously
in stone
to
R,
(24-h
only
for
depend
to some
is the
formers.
after-loading
sibs
is not the first
previous
association
and
Finally,
17).
(
be
described
levels
significance
chromosome
been
is similar
others
in idiopathic sis.
men.
and
calcium
to
associated
would
1,25(OH),D3
controls.
framework LD, Gerety
susceptibility
which for
ics)
Nephrolithiasis
T, Hayashi
and
527-533,
bow-resolution
increased
showing
female
have
a sequence
increased
found
not
a decreased
than
serum
was
239:
and
stone
D3
Commun
both
restricted
24-h
hydroxyvitamin
Suda
cDNA
amplified
cab-
HF,
of
forma-
phenotypes
subjects
unaffected
in women,
higher with
This
hy-
H, Debuca cloning
test
of calcium,
been
male baseline
and
Similar
could
formation
have
lecular
calcium
stone
calcium
a moderately
with
mild
Anazawa
with
hypercalciunic
under
increased
because
excretion
that
increased
loading
renal
confirms
urine
demonstrate
is compatible
urinary
this
for
24-h
in hypencalciuric
tests)
calcium
and
families,
calcium
factor
increased
pattern
finding
group
risk
have
24-h
and
in suggesting
a calcium
This
absorption
most
risk
also
after
calciunia.
(2)
women)
absorption
fasting
increased ones,
an important
sibs
(particularly
cium
have
unaffected
studies
might
Affected
and
men,
over
case-control
peroxabunia
In
particularly oxabate
Calcium
in
stone. P. Chillaron
Craig
1W, Thakker
inherited
kidney
J Cii,i
DG:
Chloride
Invest J, Chillon
B, P.
RV: stone
channels
99: 819-821, M, Gallucci
A disand
1997 M,
432
Journal
Rousaud
P, Estivill
caused
by mutations Nat
Rossiter
13.
and
and
F,
Coe
Eur
of
1994
Hypoxanthine-guanine
phosphoribo-
syndrome
Bases
Bases
of
and
Inherited
gout.
In:
F, Parks
I, Moore 300:
Pak C, Kaplan
R, Bone
urias.
Vol.
hypercalciunia.
Am
J Med
Levy
25-32,
Adams
administration
I, Waters
0: A simple
and
renal
20.
I, Porat
tions 2 1.
A, Gantt
cium
in healthy and
man.
serum of
752-759, Broadus
Kidney
II,
Insogna
D concentrations
Lang
men.
F, Baylink
MR.
Deftos
36.
Ellison
AF,
humans:
Studies
in patients Metab Insogna
N
LI, Bone
EngI
H, Pak CY:
D, Ivey
The
40.
in healthy
299-306,
subjects
in calcium-stone
hyperparathyroidism.
42.
A, Dreyer
rate
of
absorptive
hypercalciuria.
B, Ellison
A, Gertner
I ,25-dihydroxyvitamin J
Cliii
D
of in and
43.
Endocrinol
I: Elevated
Metab
ketoconazole dihydroxyvitamin crinol Metab
Preminger
to probe
GM,
the
Adams
pathogenetic
D in absorptive 75: 1446-1452,
BV,
Otey
44.
major
locus
Tiret
L, Rigat
importance
hypercalciunia. 1992
of
J Clin
gene
Use of
I ,25Endo-
region
and
Dizier
poly-
1995
test for linkage
insulin
dependent
dia-
1993
D deficiency
(vita-
and Bone University
EE:
Pseudo-vitamin
D defi-
D I alpha-hydroxylase cells. J Cliii Endocrinol
1995
F, Harmeyer
I: Absence activity
Calcif
Tissue
d#{233}s#{233}quilibre de liaison. K, Kuida
in Utah
B, Visvikis
controls
with 1986 7:
R: Hypertension
pedigrees:
Genet
5, Breda
25-hy-
M#{233}decine/Sciences
H, Williams
Aiiz J Hum
of renal
in a pig strain tnt 38: 87-94,
43:
14-22,
C, Corvol
and
Evidence
for
1988
P. Cambien
F,
from combined segregation and linkage of the angiotensin b-converting enzyme
plasma
ACE
levels.
Am
J Hum
Genet
51:
1992
MH,
Hill M, lames
AW, Demenais
gene
response Wikwall
for
high
A, Faux
I, Ryan
F. Cookson
IgE
levels
G, be Souef
P. Lathrop
W: Detection
of a recessive
independently
of specific
acting
to allergens. Genet Epidemiol 12: 93-1 05, 1995 K, Axen E, Postlind H, Araya Z, Norlin M, Furster
1997,
p 144
Parks
IH,
Coe
FL,
sponge
1091, 1982 Zerwekh IE,
Hoopes Genetic idiopathic I996
777-787,
E: Pseudovitaruin
Strauss
kidney
Hughes
M, Nasonkin
AL:
MR.
Reed
I, Pak
RR,
Reid
analysis
R, Thakker of the
hypercalciunia
nephrolithiasis
N EngI
BY,
CY:
hypercalciuric lAbstract].
NA,
for normal
and
and
306:
1088-
Heller
HI,
vitamin
D
genotype in absorptive 80: 2960-2965, 1995
Metab
RV,
J Med
Breslau
Evidence acid
C:
D3 1 a-hydroxylases in D, Strasbourg, France,
Calcium
in women.
receptor messenger nibonucleic hypercalciuria. J Cliii Endocrinol 45.
of
or more
52: 506-516,
Genet
A, Delvin
inheritance.
gene
one
1 15-123
F: Evidence, that a variant
Leruke
with
6 1 : 490-
I, Pak CY:
56:
Genet
countertransport
medullary
Endocrinol
in patients
pp
Arabian
Le
clearance
for the analysis
and
Evidence for multiple 25-hydroxyvitamin the kidney. In: 10th Workshop on Vitamin
1977
K, Broadus
NA,
I:
major
formers
J Clin
.
method loci
Absence of 25-hydroxyvitaruin in human placenta decidual
M, Musk
M:
importance D levels
of
57: 439-454,
In: bnborn Errors f (‘alcium by Bickel H, Stern I, Baltimore,
1976, FH,
197-205,
Med
production
Breslau
Press,
Soubrier analysis,
41
hyper-
analysis
Genet
W: Transmission
Am J Huni
R, Heierli
sodium-lithium
495, 1985 27.
A, Illing
J Huii
insulin
(IDDM).
39.
1977
D in idiopathic
of A
1994 Release Case West-
of creatinine
trait
R, Ewens
161-168, 1991 Hasstedt S, Wu L, Ash
and
I, Haussler
construction (MultiMap):
16: 3 1-4 1 , I 976
likelihood
Am
Feingold
role
of intestinal
hyperparathyroidism 59: 756-760,
R, Sherrard
loci.
38.
D 3 1 1:
Med
J
D in the mediation
1 ,25-dihydroxyvitamin Cliii
with primary
45:
BE:
in French
sib-pair
Am J Hum
between
Metab 80: 2255-2258, Winkler I, Schreiner
26:
Dreyer
effect
1994
Prediction
A powerful
The
mellitus
ciency: activity
cab-
bnt
MH:
droxycholecalciferol-l-hydroxylase vitamin D-dependent rickets.
as deter-
Kidney
90: 955-962, 1977 Gray R, Wilz D, Caldas A, Lemann II: The phosphate in regulating plasma l,25-(OH),-vitamin J Lab
ID:
Gbonieux
hit
1,25-dihydroxyvitamin
in primary J Cliii Invest
D, Nielsen
serum
R.
control of hypercalciunia.
25-dihydroxyvitamin
Increased
26.
D: Dietary
Ohio,
Nephron
R, McGinnis
(ACE)
1984 RA, Haussler
calciuria.
25.
1983
R, Cheung
in healthy
KL,
hyperabsorption of calcium absorptive hypercalciunia. Shen
Kidney
but 24: 555-566,
balance
for disordered in absorptive
of I alpha,
24.
men.
Gray
l,25-(OH)2-vitamin
calcium
AE,
73-80, Kaplan
in healthy
F:
Pseudo-
1996
multipoint
traits.
Gault
ruin D dependency). Metabolism, edited
1984
Evidence production 23.
of nephro-
founder
A: Automated expert system
Cleveland,
creatinine.
marker
Prader
37.
W, Lemann
minants 22.
35.
Park evaluation
the
populations:
59: 633-643,
E: Complete
disequilibrium
betes
W, Gray R, Cheung H, Lemann II: Bone resorption by elevated serum 1,25 (OH)2 vitamin D concentra-
Maierhofer
DW,
serum
Spielman
1982 B, Pak C: Ambulatory
and
and quantitative
disequilibrium:
A, Parks
metabolism
University, L, Lander
morphic 34.
1982
Maierhofer stimulated
Reserve
Kruglyak
Terwibliger
test
hypercalci-
in young
TC, Perlin M, Chakravarti linkage maps using an
Cockcroft
1975
T, Strauss
on calcium
21: 90-97,
Genet
linkage
resorptive
analysis
D, Zietkiewicz
E, Root A, Gborieux
1995 32.
An update of a 1980 protocol. Am J Med 98: 50-59, 1995 N. Gray R, Lemann IJ, Cheung H: Effects of calcitriol
lithiasis:
19.
72:
F, Adams-Huet
rickets
Am
qualitative
33.
C, Sherwood L: Effects of low-calcium diet on urine calcium excretion. parathyroid function and serum 1,25 (OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects. 18.
D-deficiency
from
idiopathic
497-500,
M, Crockett
vitamin
ern 3 1.
1979
H, Townsend
292:
J Med
F. Favus
disequilibrium J Hum
M, Cole
E, Pronicka
human genome linkage map. Nat Genet 6: 384-390, SAGE: Statistical Analysis ftr Genetic Epidemiology, 2.2., Department of Epidemiology and Biostatistics,
30.
The
II, 7th
D, Korab-Laskowska
I, Popowska
Linkage
Matise genetic
1980
E: Familial
337-340.
of absorptive,
N EngI
Coe
239-242,
29.
Vol.
In:
Disease,
M, Labuda
Canadians.
Disease,
lithiasis.
oflnherited
133:
N EngI J Med
Labuda
E, Weissenbach
in the transport
2,8-dihydroxyadenine
J Pediatr
28.
M: Cystinunia
Ed., edited by Scriver C, Beaudet A, Sly W, Valle D, New York, McGraw-Hill, 1995, pp 1707-1724 Mehes K, Szelid Z: Autosomal dominant inheritance of hyper-
for the diagnosis 17.
involved
Lesch-Nyhan
and Molecular
calciuria.
16.
CT: Molecular
ribosyltransferase
15.
a gene
B, Di Silverio
Z, Palacin
II. 7th Ed., edited by Scriver C, Beaudet A, Sly W, Valle D, New York, McGraw-Hill, 1995, pp 1679-1706 Simmonds HA, Sahota AS, Van Acker, KI. Adenine phosphoMetabolic
14.
X, Dallapiccola
6: 420-425.
deficiency:
Metabolic
Nephrology
of
A, Nunes
in rBAT,
Caskey
syltransferase The
L, Testar X, Zorzano
Genet
BIF,
Society
American
F, Zelante
Barcebo cystine. 12.
the
of
Bushinsky rat, J Am
DA,
Scheinman
a model Soc Nephrol
for
SI: human
7: 1598,
