Congenital Nephrogenic Diabetes Insipidus

DISEASE OF THE MONTH

Congenital

Nephrogenic DANIEL

G. BICHET,*

*Department

nephrogenic

diabetes

antidiuretic

tion,

hormone

arginine

characterization,

for

ND!:

X-linked

(>90%)

our

(AVP).

mutational

understanding

of congenital

1 15 families

with

ND!

of

two

different

hereditary

recessive

patients

have

ND!

that were

forms

NDI.

of

A majority

AVPR2

mutations:

referred

receptors

reach

or to properly the

trigger

mutant

AQP2

luminal

the cell

surface

Of

to our labo-

but are unable

an intracellular

proteins

are

membrane.

advances

described

provide diagnostic tools for physicians and open the door for the development based on gene transfer.

Cellular

Actions

Biology

of ND!

The of the

complex

of water architecture

in this

caring

for these

of therapeutic

of Vasopressin

conservation

by the human of renal

kidney

tubules

the

tion

interstitium.

gradient The

between process

the tubular of this

to the vasopressin dimensional

model

and duct

is shown

membrane

of collecting

in Figure

duct

thereby

are

increasing

of AVP

2A)

cells.

located

This

on

step

the

(AQP1

membrane

to

water are

the

that

; also

protein

permeability

members

and

final

(G.j, actistimula-

step

facilitate

known

water

in

the

kD)

was

the

first

in

mammalian

red

limbs,

water-permeable is localized in both

subcellular

level,

AQP1 that water

may

of

vacuoles.

In the basolateral and

water

channel

AQPI

are

lateral

localized

and

inner

and

to

exit

is the

ducts.

thin

routes

AQP2, of

AQP1

medullary

tubules,

membranes

AQP2

collecting

to ex-

epithelia (6). At the apical and basolateral

contrast in

shown

proximal

membranes,

Aqua-

is constitutively

entrance

In

infoldings.

in renal

cells

represent

transport.

amounts basal

renal

integral integral

protein

and

and other

membranes

transepithelial

channel cells,

of

(4,5).

channel-forming

pressed

descending

membrane.

transport

as CHIP,

of 28

of that

of a superfamily

water

brane water

from

intracellular

for

limited

vesicles

is localized

or

to both

vasopressin-regulated

It is exclusively collecting

the

vesicles

(the shuttle hypothesis) channels in basolateral

present

duct

cells

in

and

is

ND!,

antidiuretic

the renal

action

of

l-desamino-8-D-arginine and

repre-

1 ; a threewhere AVP basolateral

a cascade

into

the

apical

plasma

mem-

(Figure 1). AQP3 and AQP4 are the membranes of renal medullary col-

ducts.

collecting

AVP

or

vasopressin

(OMIM),

Johns

Hopkins

ducts

to

its

are resistant

antidiuretic

(7,8).

now well described, entity secondary AVPR2 gene (X-linked ND! [Online

This

to

analog

is a rare,

but

either to mutations in the Mendelian Inheritance in

University,

Baltimore,

MD;

3048001), which codes for the antidiuretic (V.,) receptor, or to mutations in the AQP2 gene (autosomal recessive ND! [OMIM, Johns Hopkins University; MIM No.: No.:

MIM

222000]),

which

channel (9-1 our laboratory eight

Centre, H#{244}pital du Sacr#{233}tients Montreal, Quebec, Canada

1046-6673/0801 2- 195 1$030010 Journal of the American Society of Nephrology Copyright © 1997 by the American Society of Nephrology

leads

as a molecular

plasma

Germany.

of G-protein of cAMP,

function

and Correspondence to Dr. Daniel G. Bichet. Research Coeur de Montr#{233}al,5400, Boulevard Gouin West. H4J 1C5.

the

proteins

In congenital

is its binding

initiates

A-that

channels

membrane

Man action

activation production

cyclase,

kinase

Berlin,

action of AVP, i.e., the exocytic insertion of spechannels, AQP2, into the luminal membrane,

water

lecting an

system

V2 receptor (AVPR2 in Figure of the vasopressin V2 receptor

is docked

renal

tubules hormone down

cells

protein

channels

the surrounding

multiplication

collecting

of

These

concentra-

passively

fluid

counter

the action of AVP on principal sented in Figure 1. The first step in the antidiuretic

urinary

Pharmakologie,

of events-receptor-linked vation of adenylyl tion

ROSENTHALt

H#{244}pitaldu Sacr#{233}-Coeur de Montr#{233}al,

diffusely distributed in the cytoplasm in the euhydrated condition, whereas apical staining of AQP2 is intensified in the dehydrated condition or after vasopressin administration. These observations are thought to represent the exocytic insertion of preformed water

is a function

within

WALTER

Centre,

Molekulare

principal

and Molecular

The major action of AVP is to facilitate by allowing water to be transported

osmotic

review patients

strategies

medulla ( I ). The principal cells of the renal collecting are responsive to the neurohypophyseal antidiuretic AVP.

AVP

cAMP signal. Similarly, and cannot be expressed at

misrouted

The

to bind

fir

porin-l

ratories in Montreal and Berlin, 105 families had A VPR2 mutations and 10 had AQP2 mutations. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant

and

Research

antidiuretic cific water

identifica-

and the vasopressin[AQP2]), provide the

different

autosomal

congenital

is a rare

The

analysis

of two

and

ND!

tForschungsinstitut

(NDI)

genes, i.e., the AVP receptor 2 gene (AVPR2) sensitive water channel gene (aquaporin-2 basis

OKSCHE,t

by the failure to concenplasma concentrations of the

vasopressin

and

and

insipidus

of the kidney characterized urine despite normal or elevated

Insipidus

Universit#{233} de Montr#{233}al and

Canada;

disorder trate

ALEXANDER

of Medicine,

Montr#{233}al, Quebec,

Congenital

Diabetes

codes

for

the

vasopressin-dependent

water

1). Of98 families with congenital NDI in Montreal, 90 families have A VPR2 have

AQP2

mutations.

Most

of

the

referred to mutations

affected

AVPR2 or AQP2 mutations) have a full type characterized by the inability to increase the osmolality value above the plasma osmolality value a pharmacological infusion of l-desamino-8-D-arginine sopressin

(with

(7).

Only

three

AVPR2

mutations

paphenourinary during Va-

are characterized

Journal

1952

Thick

of the American

ascending

limb

Society

of Nephrology

of Henle

Na

Principal

3Na

,. K

cell of the

collecting

2K

duct

AQP

1120

Thin limb

of Henle AQP4

/“

Inner medullary collecting duct

4OOH Figure

1. Schematic

reabsorption Na-K-2C1

(AVP) the

increases

permeability

membrane.

AVP

is characterized

terminating cAMP.

of the free

G0-chain

Cytoplasmic

basolateral the inner with

areas

involved

the adenylyl the water

Vasopressin

also

interstitium.

collecting

duct

with

a less

channel

and

thin

catalyst.

proteins

the water permeability

increases This

follows

mechanism.

V2 receptor

concentration

transmembrane

A cAMP-dependent

(Top

domains

separated

activation

of the

protein

as homotetrameric

(a G-protein

of cAMP.

of the terminal

is provided

descending

limbs

by urea of short

transporters loops

Left

kinase

by a large

complexes)

are fused

part

of the collecting

(represented

of Henle

here

express

duct with

G-protein

a urea

and and

membrane

water channels are are expressed on the resulting

in movement

10 transmembrane

transporter

loop (G)

of the generated

to the luminal

to urea,

on

of adenylyl

cytoplasmic

is the target

The

receptor)

topology

heterometric

A (PKA)

Panel)

medulla. The vasopressin

linked

The

permeability of this membrane. When vasopressin is not available, returns to its original low rate. Aquaporin-3 (AQP3) and AQP4

the permeability

process

intracellular

receptor-linked

(represented

concentrating

countercurrent multiplication within the renal limb is shown. (Right Panel) Plasma arginine

to the vasopressin

the

putative

of cAMP cyclase

is bound

increasing

of six hydrophobic

Generation

increasing and water

The hormone

cyclase,

in the urinary

initiate ascending

domains).

(reprinted

from

Both

reference

2

permission).

by

a mild

phenotype

possibility

of increasing

mosmol/L

during

sodium some (14,

human region

15). 1

amino

The

less

Xq28

and

sequence with

test

than

receptor

150

gene has

of

clinical

osmolality

a dehydration

V,

acids

severe

urinary

concentration

The

37

repeats

carrying thereby process.

the medullary

medullary

selected

ducts:

adenylate

tail. with

vesicles

membrane. into

tandem

intracellular

in response to vasopressin, retrieved by an endocytic of urea

with

in collecting activates

by two

in a large

interaction

of the nephron

but not water, from the ascending limbs of Henle, (inhibited by bumetanide) in the medullary thick

water

basolateral

cyclase

representation

of NaC1, cotransporter

three the

a structure

with

a concomitant

mEq/L

AVPR2 exons

cDNA typical

disease

to approximately

and

the 400

plasma

12ql3

(12,13). is located and

predicts

two

protein-coupled receptors with seven transmembrane, four extracellular, and four cytoplasmic domains (16) (Figure 2A). The human AQP2 gene is located in chromosome region (G)

small

a polypeptide

of guanine-nucleotide

and has four

to code

in chromo-

into

introns of

six

two

repeats

membrane-spanning

located

exons

for a polypeptide

intracellularly,

oriented

and

three

of 271 at

introns

amino

1 80#{176} to each

domains, and

(10,1

acids

conserved

with

1). It is predicted

that other

both

is organized and terminal

asparagine-proline-

that

has ends

Congenital

ND!

1953

B 30

-

20

-

I

I

10

-

p %

//-

I

I

I

11

10

9

AVP

Figure

2. (A) Ribbon

The positioning

representation

of the AVP

of transmembrane

transmembrane

helices

extracellular

side

to the model

published

domains

are shown

in red,

and

is at the top of the image. by Mouillac

et a!.

receptor

I through

2 (AVPR2).

(3)

and

hypothetical

pertaining

extracellular

model to the

Institutes

AVP

of Health

but failed

the first

three

Grant

RR-01081).

to stimulate transmembrane

(B) Expression

adenylate

cyclase

, receptor.

domains

of the R137H Inset

(28).

shows

and, as a result, males phenotype characterized

is located

7

is supposed

in L cells.

The

of the

6

and

to the cell membrane surface. surface of the receptor. The

The

model

is oriented

its V, receptor

to be completely

such

is constructed

embedded

that

the

according a 1 5 to 20 A

into

R 137 residue is represented. This image was San Francisco. CA: supported by National

R137H

missense

mutant amino

had acid

unaltered

affinity

in a planar

for tritiated

representation.

Only

are represented.

natremia,

The

Characteristics of A VPR2 Mutations, Population Genetics, Ancestral Mutation and de novo Mutations, and Mechanisms of A VPR2 Mutations gene

AVP

in purple.

AVP

The localization of the University of California. mutant

Clinical Incidence,

AVPR2

are shown between

the localization

alanine (Asn-Pro-Ala) boxes (Figure 3). These features are characteristic of the major intrinsic protein family. There is 48% amino acid sequence identity between AQP2 and AQPI (I I).

The

loops

of interaction

cleft defined by the transmembrane helices 2 through 7 of the receptor. produced using the MidasPlus program (Computer Graphics Laboratory,

8

M)

is a side view from a direction parallel when viewed from the extracellular

7 is counterclockwise

the intracellular This

This

(-log

in

chromosome

who have an A VPR2 by early dehydration

region

blood adequate

organs.

Mental

classical

lack

have

episodes,

hyper-

of

mosome a

manifestations

of X-linked

can

perfusion

and

to

and

inactivation.

first

a degree

retardation

and

The

and

onset recessive

of severity

ND!

are

life.

lower

insufficient

to

and

renal

are and

variable

skewed of

other

failure

diagnosis

exhibit

because

of

they

kidneys.

of a late females

week

that

brain,

polydipsia

of autosomal

ND!.

the

severe

consequences

Heterozygous

polyuria

so

to the

physical

“historical”

as

be

pressure

oxygenation

treatment.

of

as early

episodes

sustain

grees Xq28

hyperthermia

arterial

the

mutation

and

dehydration

de-

X chrothe

similar

clinical to those

of the American

Journal

1954

Society

Nephrology

of

Ri 870 Loop E

extracellular

T 26M 68M

R85X S216P

.

intracellular G64R Loop B 1

271

NH2

Figure

3. Schematic

of hydrophobic (Asn-Pro-Ala) channels.

The its

motif

early

of the AQP2

that

in each

are

ofthe

symptomatology

severity

Bode

representation sequences

in

( I 7).

infancy

The

recognized

and

of six

two prominent

loops.

described

manifestations

the first

AQP1

of life.

The

(and

Crawford

history

given

pation;

by

erratic.

Even

the

the

of perspiration,

in warm

weather the

and

increased

condition

bouts

water

the

of

restriction

of dietary

loric

water,

loss

dwarfism

early,

with

in

will The

protein

children

the

will

ex-

retardation is a intake of large leads

Affected

children

fre-

patients

and

in

patients

with

central

(neurogenic)

with

that

C

an NPA aqueous

insufficiency and

may

could

thrombosis

be the

of the

originally

America, that

gb-

An

residing mutation

transmembrane

(23).

The

largest

is the Hopewell family, that arrived in Halifax,

an estimated males and

are based in Quebec

however, the

described

is a missense lacks

these figures ND! known

ancestors.

its members

terminus

X-linked ND! ship Hopewell

is a rare disease with four per 1 million

lO_6; X-linked

of North

was

mutation”

a receptor

six stretches

share

independent

of life with

X

It is assumed

of common

pedigree

cellular

voluntary to hypoca-

regions

progeny

“Utah

four

text)

renal

decade

dehydration

X-linked ND! of approximately

higher.

pedigree, this

quently develop lower urinary tract dilatation and obstruction. probably secondary to the large volume of urine produced ( I 8). Dilatation of the lower urinary tract is also seen in primary polydipsic

is much

Chronic first

with

(see

(17).

frequency of 7.4 of patients with

In defined or

sometimes

patient’s

intake,

infancy.

Generally, prevalence

of lens containing

of the of

is represented

proteins

( 19.20).

end

tufts

carrier number

visible fever

insipidus

merular

are

dehydration,

beginning

of episodes

symptoms.

is recognized

and

result

weight.

no

during

of hypertonic

combined salt

by the

consti-

to gain

complicated by convulsion or death. Mental frequent consequence of these episodes. The quantities

occur

be

A monomer

intrinsic

is a homotretamer

diabetes

could

show

AQP2)

and

are irrita-

failure

mutations. major

and

infants

persistent

characteristically

exaggerates

frequent

includes

fever;

patients

evidence Unless

often

unexplained

though

perience

mothers

The

by analogy

disease

ble, cry almost constantly, and, although eager to suck, vomit milk soon after ingestion unless prefed with water.

of 10 AQP2 helices.

disorder by

of the

week

identification

transmembrane

of the nephrogenic is clearly

first

during

protein

suggestive

the prevalence

patients

in these

example

is the

in Utah

(Utah

by Cannon 1 2X)

domain

7

known

regions Mormon

families); (22,23).

(L3

predictive

and

the

kindred

named after Nova Scotia,

(24). Aboard the ship were members of the descendants of Scottish Presbyterians who Ulster Province of Ireland in the 17th century for the new world in the 1 8th century.

a

on the (21).

The of

intrawith

the Irish in 1761

Ulster Scot clan, migrated to the and left Ireland

Congenital

Whereas families settled in northern second

emigration

wave,

Colchester

County,

hypothesis”

(24),

progeny This

arriving with the first emigration Massachusetts in 17 1 8, the members

of

descendants

In two

villages

diagnosed,

X-linked upheld linked

carriers

the

from

2500

in its originally ND!

patients

in Nova

30 patients has

been

proposed

cannot

it is not

clear

whether

the

Hopewell

of ND!

Scotia.

4).

been

The

diversity

groups and

at 6%

of

the

was

balanced

However,

among

X-

loss

of mutant

the W7IX

mutation

is

males,

whereas

truncated

reproduce

affected

in the

disease

that

in the from

are

gain

and

the

of

now NDI

found

with

male

compared occurs

are

ND!,

because

of the

with by

recessive

rates

patients

In X-linked

alleles

if mutation

an X-linked

for

occurs

X-linked

ethnic

Africans)

lethal

males

been (Figure

in many

consistent was

population

mutant

a rare

have

X-linked

mutations.

affected

with

or by putative

African-Americans, past

be

passengers gene

with

by recurrent of

males

AVPR2

of the

mutation

different

mutations

of the

alleles

Hopewell

families Japanese,

rareness

and

by

Seventy-two

AVPR2

(Caucasians,

American cannot be

N terminus,

America

immigrants. unrelated

disease

extracellular

carrier

mutations

more common than another AVPR2 mutation. It is a null mutation (W71X; 23,25) (Figure 4) predictive of an extremely of the

half

original

102

mortality

consisting

and the N-terminal the

disease-causing

higher

receptor

domain, Because

Scot

in

1955

loop. to North

Ulster

recessive

form.

America,

brought

reported

have

mutations found in North the Hopewell hypothesis

in North

was

(21),

other

are

estimated

transmembrane

intracellular

identified

wave.

prevalence

residing

inhabitants,

first

in

America

emigration

on the high

frequency

the numerous ND! families,

North

second

Scots

settled

the first

to the “Hopewell

in

the

mainly

carrier

Hopewell,

According

patients

of the Ulster with

and

of the

Scotia. NDI

is based

among

(2 1 ). Given

Nova most

female

assumption

passengers

wave of a

NDI

healthy

mutation.

disease

equal

in

If

do

mothers

not and

extracellular

intracellular Figure

4. Schematic

frameshift, are not

two included

mutations;

R202C,

figure.

Predicted two

amino

to the C terminus,

according

255del9.

YI24X,

SI26F,

855delG.

Y128S,

Y205C,

TM1:

V277A,

P322H, P322S, W323R. C3: by direct repeats, complementary

substitutions)

can

in the human

V2 receptor

be explained gene

are

to Sharif W71X.

V278,

and

TM13:

AI32D. V206D.

mutations.

given

as the

in the

same

Hanley

H8OR,

C11: R137H,

(40).

L83P,

RI43P,

L219R,

Q225X,

Y280C,

W284X,

A285P,

in CpG

deletions symmetric dinucleotides,

one-letter codon.

P286L,

which

large

Solid

names

include

deletions

symbols

of the

indicate domains

(TM1

to TM11)

TM1:

337delCT,

P95L.

E13: R1O6C,

P286R,

L292P,

spots

for genetic

L44F,

SI67L, 786delG,

W293X.

disease

E,,,,:

predicted assigned

1 l3delCT.

528delG. TM1: Wl645, C111: E231X, 763delA,

are hot

the

10 non-sense,

L44P,

4O2delCT,

and

location

of the

according

to the

are labeled L53R,

L62P.

Cl l2R,

S167T. E331: R181C, E242X, 8O4insG, 977delG,

18

incompletely

were

98ins28,

and insertions can be attributed to slipped sequences in the vicinity of the mutation which

36 missense,

are characterized

mutations

and transmembrane

V88M,

528de17, 753insC.

four

code. The

E1: 98del28.

D85N,

mutations,

The

(C1 to C1),

TM:

R337X. Whereas repeats and

by mutations (26).

acids mutations

of 72 A VPR2

deletion

(E1 to E1,,,), cytoplasmic

C1: 274insG,

684delTA,

and identification

and five large

different

extracellular

T204N,

834delA,

splice-site,

The

and C1: 253del35,

TM111: QI l9X,

one

indicates

nomenclature.

the N terminus

of the V2 receptor

deletions,

in the

an asterisk

conventional

L312X, favored

representation

inframe

982-2A--*G.

from TM3

RI 13W. G185C, 8O4delG, TM11:

mispairing during DNA replication (more than 50% of the single-base and

which

are relatively

common

1956

Journal

fathers,

then,

the

American

at genetic

affected males have described potential

of

equilibrium,

of

of

those

receptor

the

rhodopsin

from

too.

spread

gene,

The mutant

have

many

been

sion

mutations)

systems

has

(Figure

with

late-onset

different

light

mutations

(ap-

region

of the

2B).

studied

Most

of

using

the

expres-

in vitro

mutant

V,

receptors

truncated

coexpression

of

the

consisting

Four

of

834delA, tivity

as

binding the

six

and

W284X)

amino

AQP2

Males

increase

the

potentially

of AVPR2

gene

r

who

(Figure

oocytes

flO/)U5

alone.

with

two

for

different

mutations studies

injected

These

with

mutant

permeability,

findings

caused

by

gene.

More

trally

independent

and

secondary

to

autosomal novel

of expression

and

coworkers

derlying AQP2

we

Carrier,

for to

in the

done

with

demonstrated

of onset

symptoms forms

desmopressin responses

of the do can

with

abundant

water

and

groups without

their

analysis history

not

AQP2 AVPR2

NDI

with

the is

ancescould

be

gene. Reminisproteins, Deen major

the

cause

un-

misrouting

of

low

receptor)

is

Most

and Perspectives

disease differ

(shortly between

distinguished

elicits

extrarenal with

channel

after

birth)

the

two

by

clinical

and

forms.

(coagulation autosomal

recessive

(AQP2). the

clinical

and

the

Whereas

vasodilatory) NDI.

patients

mental

In

of

This

advantageous of these

Two

for

effect drugs

the

NDI,

become

other functional insipidus (37), other

Within

Depending

the

the

(/3-galactosidase) perfusion

(2)

rate

past

few

of out-

the

and

of the

therapy

gasgenes

based

on

can

route,

renal

seem

Unlike central diabetes (see above), and many kidney

function

observed.

naturally occurring of G-protein-coupled years.

however,

due

Thus,

be

achieved

to

with the

either

by

or by retrograde the pelvic cavity of

in proximal or

to

organ

Recent experiments gene transfer

expression artery)

to be ful-

The defect in the reabsorption with no

(1)

tubular

cells

with

mutations hormone a number

the

reporter

tubule

and medulla (retrograde infusion). mutations in the V, receptor associated

the

use

urinary

treatment

renal artery placed into

is observed via

were the first large group

the

reduce

filtration

is not

kidney

of the a catheter on

diet,

normal

against

of

changes

of

perfusion through

with

ensure

identification

adenoviral-mediated

system

by an

disturbances;

for gene

to be preserved.

that

to

a causative

a deterioration

seems

show

prevented be provided

electrolyte

or histological defects. retinitis pigmentosa

structural

integrity

V,

possible.

crucial

diseases,

progressive

the

few are obser-

to be weighed

of glomerular

congenital

prerequisites

are

may

(thiazides:

With

in

symptoms; unpublished

birth

has

of

X-linked

a mutation

from

vom-

to thrive.

with

should

indomethacin

reduction

has

identification

ND!

water

symptoms). for

the

to a low-sodium

or

effects

NDI very

is

origin, failure

families

patients

addition

side

papilla The

of

in newborns of all age

and

with clinical (D.G. Bichet.

Thus,

amounts

transfer

for in

of congenital

(thiazides)

gene

important

heterozygous

put.

(kidney

and

development

of unknown

osmolality,

carriers

intake.

development.

gene

The

However, testing:

be performed and in patients

present (35.36)

water

unrestricted

(38).

diet, episodes

should of NDI

fever

also

females

do not affected

selective infusion

become clear that congenital mutation of a G-protein-

or a water

a low-sodium

and

urine

female

receptor severely

rats

of cord

immediately

experienced

filled in both forms of congenital ND!. kidney appears to be restricted to water

autosomal

were

physical

continuing

nonobligatory

tubular

Testing,

be

in patients

both

ND!

retardation of X-linked

with a firm diagnosis of congenital ND!, with or a family history. It may also be considered in babies

responsible

AQP2

treatment

of a sample

patients

intake,

mo-

and

and mental

testing

never

fami-

to recommend

Diagnosis

These

They

indomethacin:

(3 1,32).

Perinatal

(V,

that

phenotypes

that

recessive

proteins

receptor

treated

trointestinal

coefficient constructs

in three

that

Xe-

oocytes

in the

evidence

Over the past few years, it has NDI is caused by an inactivating coupled

patients.

follow

diagnosis

the physical

by mutation

of our

normal. Gene with a family

early

diagnosis

who

of dehydration.

accomplished

congenital

allowing ND!

because

can avert

in five

diuretics

abnormal

evidence

suggest

mutations

also

had

mutations

ND!

been AQP2

that

Xenopus

conclusive

recessive

autosomal mutant

was

underlying

physicians

non-X-linked

episodes

blood

adequate

(9,10,12,30,31)

cRNA

obtained

studies

have in the

mutant cRNA had to that of normal

provide

families

cent

with

ND!. for

l2ql3.

showed

whereas

homozygosity

recently,

dominant

infants

associated

analysis

of

activity.

NDI

a mutation

expression

with both normal and permeability similar

be

and

of affected

Gene

ac-

region

to desmopressin

significance.

encourage

analysis.

constantly

avenues

congenital

homozygous

of water

injected of water

genetic

iting,

cyclase

promising

in chromosome

affected

are

Functional

coefficient

lecular

X-linked

presenting

mutations.

is located

carry

3).

with

We

vations). All complications

females who

lies

receptor.

number

response defects

clinical

analysis.

8O4delG,

V,

functional in

of adenylate

are

gene

and

described

two

the

(E242X,

Mutations

The

time

of

a polypeptide

considerable

an

stimulation

therapy

acids

regained

results

of

receptors

by

and

in vitro

AQP2

130

truncated

demonstrated

gene

can

last

the

sites

These

by

extrarenal

of the molecular

immediate

dehydration,

to the cell membrane and were intracellular compartment (8). (29) pharmacologically rescued

receptors

lack

hydrochlorothiazide.

tested were not transported thus retained within the Schoneberg and coworkers V,

is of

ND!

(27).

or dysregulation of 28 different non-sense, frameshift, deletion, been

ND!

Identification NDI

by gene of

in the

X-linked

(9,33,34).

are

one-fourth

mutations

with

and

data

the coding

found

of

others

mutations,

In

by

cases

and

These

patients

throughout

basis of loss of function V, receptors (including

or missense

navo

(26).

is caused

Here,

100).

de

We

pigmentosa.

disease

rhodopsin.

proximately

of new

mutations.

mutagenesis

retinitis

patients,

Nephrology

one-third

obtained

autosomal-dominant these

of

will be due to new ancestral mutations,

mechanisms

reminiscent

Society

cells of

the

X-linked

found in the receptors.

of diseases

were

Congenital

shown coupled

to be caused receptors.

linked

ND!,

stationary

examples night

ception,

by mutations In addition of

such

blindness,

primary

in genes to retinitis

diseases/symptoms

color

percalcemia/hyperparathyroidism,

chondrodysplasia, male noma, The

expression loss

of

of

mutant

known

inactivating

receptors

function

activity about

Progress

male

mutations

on

occurs

the

I I.

swered

the cellular

routing

in this

will

field

cell

surface. of

protein.

Here,

the

At present, for

the

the

1 3.

is

recep-

14.

on a molecular strategies based

15.

16.

Dr. Bichet is a Career Investigator of the Fonds de Ia Recherche en Sante du Qu#{233}bec. This work was supported by Grant MT-8 126 from the Medical Research Council of Canada, by the Canadian Kidney and

by

the

Fonds

de

Ia Recherche

en

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Sant#{233}/Hydro-

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