Spectrum of HNF1B Mutations in a Large Cohort of PatientsWho Harbor Renal Diseases

Laurence Heidet,* Stephane Decramer,† Audrey Pawtowski,‡ Vincent Moriniere,*‡

Flavio Bandin,† Bertrand Knebelmann,§ Anne-Sophie Lebre,‡ Stanislas Faguer,†�

Vincent Guigonis,¶ Corinne Antignac,*‡**†† and Remi Salomon* **††

*Service de Nephrologie Pediatrique, Centre de Reference des Maladies Renales Hereditaires de l’Enfant et de l’Adulte,‡Departement de Genetique, and §Service de Nephrologie, Hopital Necker-Enfants Malades, Assistance Publique–Hopitaux de Paris, Paris, France; †Centre de Reference du Sud Ouest des Maladies Renales Rares, Service deNephrologie Pediatrique, Hopital Purpan, Toulouse, France; �Service de Nephrologie et Immunologie Clinique, HopitalRangueil, Toulouse, France; ¶Service de Pediatrie, Centre Hospitalier Universitaire de Limoges, Limoges, France;**INSERM, U574, Hopital Necker, Paris, France; and ††Universite Paris Descartes, Paris, France

Background and objectives: Hepatocyte nuclear factor 1� (HNF1�) is a transcription factor that is critical for the develop-ment of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract,pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.

Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with variouskidney phenotypes (hyperechogenic kidneys with size not more than �3 SD, multicystic kidney disease, renal agenesis, renalhypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).

Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42,deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66%of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to studyprenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were themore frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1Bmutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although notsystematically investigated, were frequently associated.

Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremelyvariable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

Clin J Am Soc Nephrol 5: 1079–1090, 2010. doi: 10.2215/CJN.06810909

H epatocyte nuclear factor 1� gene (HNF1B) encodes atranscription factor that binds DNA as homodimeror as heterodimer with the related factor HNF1�.

Heterozygous mutations of HNF1B were first described in ma-turity-onset diabetes of the young type 5 (1). Renal manifesta-tions are frequently observed in patients with maturity-onsetdiabetes of the young type 5 and include a wide spectrum ofphenotypes (2). More recently, HNF1B mutations were found tobe associated with a subset of fetal bilateral hyperechogenickidneys (3) and other kidney diseases diagnosed before birth(4). Besides diabetes, nonrenal anomalies involving Mullerianand Wolffian derivatives, liver and pancreas abnormalities,

hyperuricemia with or without gout (5), and hypomagnesemia(6) have been reported.

HNF1B plays a crucial role in early development (7) andthereafter is involved in the organogenesis of several tissues,such as gut, pancreas, liver, lung, and kidney. The gene isalso transiently expressed in the neural tube and in theepididymis, vas deferens, seminal vesicle, prostate, uterus,and oviduct (7,8). During kidney development, the gene isexpressed in the ureteric bud, in the comma- and S-shapedbodies, and then in the proximal and distal tubules but not inthe glomerulus (9). Kidney-specific inactivation of Hnf1B inthe mouse leads to cystic disease, and HNF1� was shown tobind directly DNA elements that regulate the expression ofgenes whose mutations are responsible for cystic kidneydiseases (Nphp1, polaris, Umod, Pkhd1, and Pkd2) (10) or of agene identified as a candidate modifier in a mouse model ofcystic kidney disease (Kif12) (11). Here we report on HNF1Bmutation screening in a series of 377 unrelated patients whopresented with various kidney phenotypes, giving specialattention to the prenatal renal phenotypes.

Received September 24, 2009. Accepted March 5, 2010.

Published online ahead of print. Publication date available at www.cjasn.org.

L.H. and S.D. contributed equally to this work.

Correspondence: Dr. Laurence Heidet, Service de Nephrologie Pediatrique, Ho-pital Necker-Enfants Malades, 149 rue de Sevres, 75015 Paris, France. Phone:�33-1-44-49-43-82; Fax: �33-1-71-19-64-45; E-mail: laurence.heidet@nck.aphp.fr

Copyright © 2010 by the American Society of Nephrology ISSN: 1555-9041/506–1079

Materials and MethodsPatients

This is a retrospective study in which we included all cases that werenot previously reported and were tested for HNF1B mutations in tworeference centers for rare kidney diseases in France. Criteria for inclu-sion were hyperechogenic kidneys (but with size not more than �3 SD),uni- or bilateral multicystic kidney disease (MCD), renal agenesis, renalhypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial ne-phropathy not associated with UMOD mutation. Patients’ samples,medical records, genealogy, and written informed consent from patientand/or parents were sent from Pediatric, Pediatric Nephrology, Ne-phrology, or Obstetric Departments. Genomic DNA was extracted fromvenous blood or tissues collected from 377 unrelated cases (271 chil-dren, 57 adults, and 49 fetuses), 221 male and 156 female.

Prenatal ultrasonographs were available for 245 probands (usuallyperformed at 12, 22, and 32 weeks of amenorrhea) and had beenconsidered as normal in only 11 cases. Renal phenotypes before birthwere isolated hyperechogenic kidneys (not larger than �3 SD in size) in55 cases, bilateral MCD (13 cases), unilateral MCD (74 cases), unilateralagenesis (34 cases), bilateral agenesis (13 cases), renal hypoplasia (25cases), urinary tract dilation (11 cases), and cystic disease (nine cases).In 132 patients, either the result of the prenatal ultrasound was notknown or ultrasound was not performed (patients born before 1980).Renal phenotypes after birth were hyperechogenic kidneys (23 cases),unilateral MCD (12 cases), unilateral agenesis (8 cases), renal hypopla-sia (33 cases), urinary tract dilation (2 cases), hyperuricemic tubuloin-terstitial nephritis (18 cases), unclassified cystic disease (35 cases), andonly extrarenal symptoms (diabetes and uterine abnormalities; onecase).

Patients with renal cavity dilation and/or recurrent acute pyelone-phritis had voiding cystourethrogram. GFR was estimated by the Mod-ification of Diet in Renal Disease (MDRD) formula for adults and by theSchwartz formula for children who were younger than 16.

Molecular AnalysisQuantitative multiplex PCR amplification of short fluorescence frag-

ments (12) was performed as described previously (13) for the search ofdeletion. When deletion was not found, the nine exons and the exon–intron boundaries of the gene were screened for mutations by directsequencing as described previously (1).

Statistical AnalysisTesting for difference in proportions was performed using the �2. All

tests were two sided. P � 0.05 was considered significant.

ResultsMutations

Heterozygous HNF1B alterations, which are thought to bepathogenic, were found in 75 probands (41 male and 34 fe-male), leading to a mutation detection rate of 19.9% of testedindex cases. They consisted of a heterozygous deletion of theentire gene in 42 cases (Table 1). Parent status was studied for21 probands: deletions were de novo in 14 of 21 cases andinherited in seven of 21. Mutations that were not deletions ofthe entire gene are shown in Table 2. One patient was carryinga de novo heterozygous deletion of exon 4, which was previ-ously reported (3,13). Twenty-four different heterozygoussmall mutations (11 missense, five nonsense, five frameshift,and three splice site mutations) were found in 32 probands.Parent status was studied for 20 of them. Mutation were shown

to be de novo in eight of 20 cases and to be inherited in 12 of 20cases; 18 were novel. Except for the mutation affecting theinitiator codon, all missense mutations were localized in theDNA binding domain (Figure 1), were modifying a conservedamino acid, and were predicted to be probably damaging bythe Polyphen program (14). In some families, there was afather-to-son transmission, in agreement with an autosomaldominant mode of inheritance (see proband 64 as an example).

Renal and Extrarenal PhenotypePatients for Whom Prenatal Ultrasound Was AvailableIn 245 cases tested for HNF1B mutation, we were able to go

back to the prenatal ultrasound. Mutations were identified in 56of them.

Prenatal phenotype in patients with HNF1B mutation wasisolated bilateral hyperechogenic kidneys with normal or mod-erately enlarged size in 34 cases, including one termination ofpregnancy (TOP) because of an associated oligo-anamnios.Evaluation of these patients at last follow-up showed renalfailure with GFR �80 ml/min per 1.73 m2 (range 32 to 61ml/min per 1.73 m2) in eight patients (1 months to 14 yearsold), GFR �80 ml/min per 1.73 m2 in 20 patients (1 to 17 yearsold), and unknown in five patients. Five patients experiencedtransitory renal failure at birth, and one developed diabetes atthe age of 17.

Other prenatal phenotypes in patients with HNF1B mutationwere bilateral MCD (leading to TOP) in two patients, unilateralMCD in eight patients, unilateral renal agenesis (with hypopla-sia and/or cysts on the single kidney) in four patients, unilat-eral renal hypoplasia in one patient, renal macrocysts in threepatients (with urinary tract dilation, pancreas hypoplasia, andTOP in one patient), and isolated upper urinary tract dilation inone patient (who developed small cortical cysts after birth). Inthree patients who presented with severe cystic dysplasia onearly ultrasound, the prenatal ultrasounds were considered asnormal. In all cases with unilateral MCD, patients developedpostnatal anomalies on the contralateral kidney. In the casewith unilateral hypoplasia, cysts developed on the hypoplastickidney after birth

Patients for Whom Prenatal Ultrasound Was not AvailableIn 132 patients who were tested for HNF1B mutation, we

were not able to go back to prenatal ultrasound (either theresult of it was not known, or ultrasound was not performed).We found an HNF1B mutation in 19 of them, including 10 whowere tested during adulthood, six of whom had a family his-tory of renal diseases. Four adult probands had cystic renalhypoplasia (associated with hypomagnesemia, gout, and a di-abetes that occurred at 42 years in one and with gestationaldiabetes in another). Two had hyperechogenic kidneys withmicrocysts. One had solitary kidney and early gout, and an-other one had hyperuricemic interstitial nephropathy. One fe-male born from consanguineous parents developed unclassi-fied renal cystic dysplasia with uterus agenesis, imperforatedvagina, cleft palate, and mental retardation. One presentedwith diabetes at the age of 31 and bicornuate uterus. Fouradults (aged 29 to 35 years) had normal renal function and five(aged 28 to 33 years) had reduced GFR (65 ml/min per 1.73 m2

1080 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010

Tab

le1.

Phen

otyp

esin

prob

and

sw

ith

com

plet

eH

NF1

Bd

elet

ions

Prob

and

sPr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Del

etio

nIn

heri

tanc

e

1N

orm

alul

tras

ound

Lar

geki

dne

ysw

ith

num

erou

sbi

late

ral

cyst

s,pr

eter

min

alre

nal

failu

reat

8m

onth

s;fa

ther

wit

hre

nal

hypo

plas

ia,G

FRun

know

n

ND

(par

ents

not

test

ed)

2N

orm

alul

tras

ound

Hyp

erec

hoge

nic

and

cyst

icki

dne

ys,n

orm

alG

FRat

6ye

ars

De

novo

3B

ilate

ral

hype

rech

ogen

icki

dne

ysH

yper

echo

geni

c,no

rmal

-siz

edki

dne

ys,n

orm

alG

FRat

10m

onth

sN

D(p

aren

tsno

tte

sted

)

4B

ilate

ral

hype

rech

ogen

icki

dne

ysH

yper

echo

geni

cki

dne

ys,m

ulti

ple

mic

rocy

sts,

CR

F(G

FR29

at6

year

s);m

othe

rw

ith

rena

lcy

sts.

Del

etio

nin

the

mot

her

5B

ilate

ral

hype

rech

ogen

icki

dne

ysH

yper

echo

geni

c,no

rmal

-siz

edki

dne

ys,m

icro

cyst

s,no

rmal

GFR

at5

year

sN

D(p

aren

tsno

tte

sted

)

6U

nila

tera

lhy

popl

asia

Uni

late

ral

hypo

plas

iaw

ith

cyst

s,no

rmal

GFR

at2

year

sD

eno

voFa

ther

and

pate

rnal

gran

dm

othe

rw

ith

rena

lcy

sts

7B

ilate

ral

hype

rech

ogen

icki

dne

ysSm

all

cyst

icki

dne

ys,n

orm

alG

FRat

3ye

ars

ND

(par

ents

not

test

ed)

8B

ilate

ral

hype

rech

ogen

icki

dne

ysN

orm

al-s

ized

kid

ney

wit

hco

rtic

alcy

sts

�le

ftPU

JOhy

peru

rice

mia

,nor

mal

GFR

at5

year

sN

D(p

aren

tsno

tte

sted

)

9U

nila

tera

lM

CD

,con

tral

ater

alcy

sts

Uni

late

ral

MC

D,c

orti

cal

cyst

son

cont

rala

tera

lki

dne

y,hy

peru

rice

mia

,ele

vate

dliv

eren

zym

es,n

orm

alG

FRat

10ye

ars

ND

(par

ents

not

test

ed)

10B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

cort

ical

cyst

s,no

rmal

-siz

edki

dne

y,no

rmal

GFR

at17

mon

ths;

fath

erw

ith

rena

lhy

pod

yspl

asia

,GFR

unkn

own;

pate

rnal

gran

dfa

ther

has

CR

F;pr

evio

usT

OP

for

MC

Dan

dan

amni

osin

the

mot

her

ND

(par

ents

not

test

ed)

11N

DD

iabe

tes,

bico

rnua

teut

erus

TO

Pin

the

past

beca

use

ofan

amni

os,n

orm

alG

FRat

adul

tag

e;d

iabe

tes

insi

ster

san

dfa

ther

Del

etio

nin

the

fath

er

12B

ilate

ral

hype

rech

ogen

icki

dne

ysFe

wcy

sts,

unkn

own

GFR

De

novo

13U

nila

tera

lM

CD

,con

tral

ater

alhy

pere

chog

enic

kid

ney

Cys

tsin

the

sing

leki

dne

y,no

rmal

GFR

at9

year

sN

D(p

aren

tsno

tte

sted

)

14B

ilate

ral

hype

rech

ogen

icki

dne

ys,o

neco

rtic

alcy

stH

yper

echo

geni

cla

rge

(�2

SD)

kid

neys

,CR

F(u

nkno

wn

GFR

)at

1m

onth

De

novo

15N

DC

ysti

cki

dne

yd

isea

se,u

teri

neag

enes

is,i

mpe

rfor

ated

vagi

na,

men

tal

reta

rdat

ion,

norm

alG

FRat

29ye

ars

ND

(par

ents

not

test

ed)

16B

ilate

ral

pelv

icd

ilati

onB

ilate

ral

PUJO

,uni

late

ral

smal

lco

rtic

alcy

sts,

norm

alG

FRat

14m

onth

sD

eno

vo

17B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

cort

ical

cyst

s,no

rmal

GFR

at3

year

s;br

othe

rw

ith

pelv

icki

dne

yan

dPU

JO;m

othe

rw

ith

norm

alki

dne

ysan

dno

rmal

GFR

,lef

the

pati

cag

enes

is,p

ancr

eas

head

hypo

plas

ia,b

icor

nuat

eut

erus

Del

etio

nin

the

mot

her

Clin J Am Soc Nephrol 5: 1079–1090, 2010 Renal Phenotypes and HNF1B Mutations 1081

Tab

le1.

cont

inue

d

Prob

and

sPr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Del

etio

nIn

heri

tanc

e

18B

ilate

ral

hype

rech

ogen

icki

dne

ysFe

wcy

sts,

norm

al-s

ized

hype

rech

ogen

icki

dne

ys,n

eona

tal

rena

lfa

ilure

,nor

mal

GFR

at20

mon

ths;

mot

her

wit

hcy

sts

and

gest

atio

nal

dia

bete

s

Del

etio

nin

the

mot

her

19B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

cort

ical

cyst

s,no

rmal

GFR

at5

year

s;m

othe

rw

ith

rena

lcy

sts

and

seve

rech

oles

tasi

sD

elet

ion

inth

em

othe

r

20N

DB

ilate

ral

cyst

s,no

rmal

GFR

at11

year

sN

D(p

aren

tsno

tte

sted

)21

Bila

tera

lhy

pere

chog

enic

kid

neys

,cor

tica

lcy

sts

(MR

I),d

iaph

ragm

atic

hern

ia

Ded

iffe

rent

iate

dki

dne

ys(5

4an

d58

mm

)w

ith

cyst

s,ac

ute

rena

lfa

ilure

atbi

rth,

GFR

40m

l/m

inpe

r1.

73m

2at

2m

onth

s

De

novo

22B

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

cyst

s,ol

igoa

mni

os

TO

P;re

nal

hist

olog

ysh

owed

cyst

icd

ilati

onof

near

lyal

lgl

omer

uli

wit

hco

llaps

edfl

ocul

us,g

lom

erul

arcy

sts

wer

elin

edby

fibr

osis

,int

erst

itia

lfi

bros

isw

ith

rare

fied

tubu

les

De

novo

23N

DB

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts,

norm

alG

FRat

17ye

ars

De

novo

24N

DB

ilate

ral

cort

ical

mic

rocy

sts,

bico

rnua

teut

erus

,dia

bete

s,no

rmal

GFR

at20

year

sN

D(p

aren

tsno

tte

sted

)

25N

DB

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts,

norm

alG

FRat

3ye

ars

ND

(par

ents

not

test

ed)

26B

ilate

ral

hype

rech

ogen

icki

dne

ys,p

elvi

cd

ilati

onB

ilate

ral

hype

rech

ogen

ichy

popl

asti

cki

dne

ys,u

nkno

wn

GFR

,m

icro

cyst

sin

mot

her

Del

etio

nin

the

mot

her

27N

DB

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts,

CR

F(G

FR65

at30

year

s)N

D(p

aren

tsno

tte

sted

)

28B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ysC

RF

(GFR

40at

3ye

ars)

ND

(par

ents

not

test

ed)

29N

DB

ilate

ral

hype

rech

ogen

icki

dne

ysco

rtic

alm

icro

cyst

s,no

rmal

GFR

at35

year

s;m

othe

rw

ith

type

2d

iabe

tes

ND

(par

ents

not

test

ed)

30N

DB

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts,

norm

alG

FRat

6ye

ars;

mic

rocy

stic

sole

kid

ney

inm

othe

rN

D(p

aren

tsno

tte

sted

)

31B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ys,C

RF

(GFR

35at

1ye

ar)

ND

(par

ents

not

test

ed)

32B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ys,d

iabe

tes

at17

year

s,no

rmal

GFR

at20

year

sN

D(p

aren

tsno

tte

sted

)

33B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ys,n

orm

alG

FRat

1ye

arD

eno

vo

34U

nila

tera

lM

CD

,oth

erki

dne

yhy

pere

chog

enic

Uni

late

ral

MC

D,o

ther

kid

ney

hype

rech

ogen

icw

ith

pelv

icd

ilati

on,n

orm

alG

FRat

3ye

ars

De

novo

35B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ys,n

orm

alG

FRat

15ye

ars

De

novo

1082 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010

to end-stage renal failure), and renal function was unknown forone.

We found an HNF1B mutation in nine patients who weretested during childhood, two of whom had a family history ofrenal disease. Eight probands had hyperechogenic kidney andcysts and one hypoplastic kidney and/or uterus anomalies (n �

2) and/or pancreatic hypoplasia (n � 1). One developed dia-betes at the age of 20 years. Renal function was normal in sixpatients (aged 3 to 20 years) and altered three times (aged 4 to15 years).

Genotype–Phenotype CorrelationThe severity of the renal disease that is associated with

HNF1B mutation was extremely variable (from prenatal severerenal failure to normal renal function in adulthood). The type ofmutation (deletion of the whole gene; missense mutation; ortruncating mutation because of nonsense, frameshift, or splicemutation) was analyzed according to the renal phenotype forthe 75 probands who carried an HNF1B mutation, as well as forother affected family members when their kidney phenotypewas known (Figure 2). The percentage of each type of mutationwas not statistically different when the group of patients whohad prenatal hyperechogenic kidneys was compared with agroup that included all other patients. We also looked for arelation between the type of mutation and the severity of thedisease in terms of renal failure, independent of the type ofrenal disease. The patients with severe and early renal failure(six patients with TOP for oligohydramnios and six patientswith terminal or preterminal renal failure that occurred beforethe age of 4 years) were associated either with deletions (sevenpatients), truncating mutation (three patients), or missense mu-tations (two patients), a figure that is not different from theproportion of each type of mutation in all patients. Figure 3shows the number of patients with and without renal failure foreach type of mutation. The proportion of patients with renalfailure at last follow-up was significantly (P � 0.012) higher inpatients who carried a truncating mutation than in patientswho carried an HNF1B deletion; however, for unknown rea-sons, patients with truncating mutation were older than pa-tients with gene deletion at last follow-up. This age differencemay account, at least in part, for the different severity of therenal failure.

DiscussionTo our knowledge, we report here the largest series of phe-

notypic and genetic analysis of patients who harbor renal dis-eases that are associated with HNF1B mutations. We screened377 unrelated patients and identified an HNF1B mutation ordeletion in 75 unrelated cases: 10 adults and 65 children orfetuses. This rate of mutation (19.9%) is not significantly differ-ent from that (23%) recently reported in a smaller cohort ofchildren with renal malformation (6). Going back to the prena-tal ultrasound when available, we report the renal phenotypesbefore birth in patients with HNF1B mutation and analyzed theevolution of their renal function.

We had information regarding prenatal ultrasound for 245patients, and this study confirms our previous finding thatT

able

1.co

ntin

ued

Prob

and

sPr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Del

etio

nIn

heri

tanc

e

36B

ilate

ral

hype

rech

ogen

icki

dne

ys�

unila

tera

lm

acro

cyst

s

Bila

tera

lhy

pere

chog

enic

kid

neys

�un

ilate

ral

mac

rocy

sts,

CR

F(G

FR55

at3

year

s)D

eno

vo

37U

nila

tera

lM

CD

,oth

erki

dne

yhy

pere

chog

enic

Uni

late

ral

MC

D,h

yper

echo

geni

cki

dne

y,no

rmal

GFR

at6

year

sD

eno

vo

38B

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts

Bila

tera

lhy

pere

chog

enic

kid

neys

,cor

tica

lm

icro

cyst

s,no

rmal

GFR

at6

year

sD

eno

vo

39U

nila

tera

lag

enes

isSi

ngle

hype

rech

ogen

icki

dne

y,co

rtic

alm

icro

cyst

s,no

rmal

GFR

at10

year

sN

D(p

aren

tsno

tte

sted

)

40U

nila

tera

lag

enes

is,

hype

rech

ogen

icki

dne

yw

ith

mic

rocy

sts

Sing

lehy

pere

chog

enic

kid

ney,

mic

rocy

sts,

CR

F(G

FR23

at1

year

);si

ngle

kid

ney

wit

hcy

sts

inth

em

othe

r(G

FR75

at30

year

s)

Del

etio

nin

the

mot

her

41B

ilate

ral

hype

rech

ogen

icki

dne

ysB

ilate

ral

hype

rech

ogen

icki

dne

ys,u

nila

tera

lV

UR

,unk

now

nG

FRN

D(p

aren

tsno

tte

sted

)

42N

DB

ilate

ral

hype

rech

ogen

icki

dne

ys,c

orti

cal

mic

rocy

sts,

norm

alG

FRat

3ye

ars

ND

(par

ents

not

test

ed)

CR

F,ch

roni

cre

nal

failu

re;M

RI,

mag

neti

cre

sona

nce

imag

ing;

ND

,not

don

e;PU

JO,p

elvi

-ure

teri

cju

ncti

onob

stru

ctio

n;V

UR

,ves

icou

rete

ral

refl

ux.

Clin J Am Soc Nephrol 5: 1079–1090, 2010 Renal Phenotypes and HNF1B Mutations 1083

Tab

le2.

Mut

atio

nsan

dph

enot

ypes

inpa

tien

tsw

ith

HN

F1B

mut

atio

nsth

atar

eno

tco

mpl

ete

del

etio

ns

Prob

and

sN

ucle

otid

eC

hang

ePr

otei

nC

hang

eE

xon

(Int

ron)

Ref

eren

cePr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Mut

atio

nIn

heri

tanc

e

43c.

3G3

Ap.

Met

1Ile

1T

his stud

yB

ilate

ral

cort

ical

cyst

sB

ilate

ral

cort

ical

mic

rocy

sts,

norm

alG

FRat

7ye

ars;

fath

erw

ith

rena

lcy

sts

Mut

atio

nin

the

fath

er

44c.

3G3

Ap.

Met

1Ile

Bila

tera

lco

rtic

alcy

sts

Bila

tera

lco

rtic

alm

icro

cyst

s,no

rmal

GFR

at7

year

s;fa

ther

wit

hd

iabe

tes

and

rena

lcy

sts

Mut

atio

nin

the

fath

er

45c.

211

del

AA

GG

GC

Cp.

Lys

71fs

1T

his stud

yN

DH

ypod

yspl

asti

cki

dne

ysw

ith

mic

rocy

sts,

GFR

45at

28ye

ars;

fath

erw

ith

hype

ruri

cem

icne

phro

path

y(G

FRun

know

n)

Mut

atio

nin

the

fath

er

46c.

232G3

Tp.

Glu

78X

1T

his stud

yN

orm

alul

tras

ound

Bila

tera

lco

rtic

alcy

sts,

ESR

Fat

3m

onth

sD

eno

vo

47c.

232G3

Tp.

Glu

78X

1M

CD

�2

TO

P;se

ptat

edut

erus

ND

48c.

322

del

Gp.

Ala

108f

s1

Thi

s stud

yN

DH

yper

uric

emic

neph

ropa

thy,

ESR

Fat

33ye

ars;

fath

erw

ith

hype

ruri

cem

icne

phro

path

y(w

ith

kid

ney

graf

t)an

dd

iabe

tes

Mut

atio

nin

the

fath

er

49IV

S134

5–1G3

A(1

)T

his stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lco

rtic

alcy

sts,

neon

atal

rena

lfa

ilure

,no

rmal

GFR

at8

year

s

ND

50IV

S134

5–1G3

A(1

)U

nila

tera

lag

enes

is�

hype

rech

ogen

icki

dne

y

Sing

lehy

pere

chog

enic

kid

ney

�C

RF

(GFR

25at

17ye

ars)

ND

(par

ents

not

test

ed)

51c.

452C3

Gp.

Ser1

51C

ys2

Thi

s stud

yU

nila

tera

lM

CD

Uni

late

ral

MC

Dan

dco

rtic

alcy

sts

onth

eot

her

kid

ney,

norm

alG

FRat

6ye

ars

ND

52c.

476C3

Tp.

Pro1

59L

eu2

Thi

s stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Isol

ated

hype

rech

ogen

icki

dne

ys,u

ltra

soun

dno

rmal

ized

(siz

ean

dec

hoge

nici

ty)

at10

mon

ths,

norm

alG

FRat

10m

onth

s

ND

1084 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010

Tab

le2.

cont

inue

d

Prob

and

sN

ucle

otid

eC

hang

ePr

otei

nC

hang

eE

xon

(Int

ron)

Ref

eren

cePr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Mut

atio

nIn

heri

tanc

e

53c.

494

G3

Ap.

Arg

165H

is2

(20)

ND

Smal

lhy

pere

chog

enic

kid

neys

,CR

F(G

FR16

at4

year

s);f

athe

rw

ith

rena

lfa

ilure

and

dia

bete

s

ND

54c.

494G3

Cp.

Arg

165P

ro2

Thi

s stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lhy

pere

chog

enic

hypo

plas

tic

kid

neys

CR

F(G

FR32

at10

year

s)�

panc

reat

ichy

popl

asia

De

novo

55c.

513G3

Ap.

Trp

171X

2T

his stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lco

rtic

alcy

sts,

norm

alG

FRat

11m

onth

sN

D

56IV

S254

4�

3del

AA

GT

(2)

(6)

ND

Ren

alcy

sts

and

VU

R,

norm

alG

FRat

6ye

ars;

mot

her

wit

hun

ilate

ral

cyst

san

dge

stat

iona

ld

iabe

tes,

norm

alG

FRat

30ye

ars

Mut

atio

nin

the

mot

her

57IV

S254

4�

3del

AA

GT

(2)

ND

Sing

leki

dne

y,go

ut,C

RF

(GFR

25at

65ye

ars)

;m

othe

ran

dm

ater

nal

cous

inw

ith

rena

lfa

ilure

;d

augh

ter

wit

hsi

ngle

kid

ney

ND

58IV

S254

4�

3del

AA

GT

(2)

ND

Cys

ts,C

RF

(GFR

60at

33ye

ars)

,dia

bete

s,hy

peru

rice

mia

,ele

vate

dliv

eren

zym

es,

hypo

mag

nesa

emia

;fat

her

wit

hE

SRF

ND

59c.

544C3

Tp.

Gln

182X

2(2

0)N

DH

yper

echo

geni

cki

dne

ys,

CR

F(b

utun

know

nG

FR);

dia

bete

sin

the

mot

her.

Mut

atio

nin

the

mot

her

60c.

544C3

Tp.

Gln

182X

2U

nila

tera

lM

CD

,oth

erki

dne

yw

ith

cyst

sU

nila

tera

lM

CD

,oth

erki

dne

yw

ith

cort

ical

cyst

s,no

rmal

GFR

at3

mon

ths

ND

61c.

544C3

Tp.

Gln

182X

2U

nila

tera

lag

enes

isSi

ngle

hypo

plas

tic

hype

rech

ogen

icki

dne

y,C

RF

(GFR

55at

7ye

ars)

ND

Clin J Am Soc Nephrol 5: 1079–1090, 2010 Renal Phenotypes and HNF1B Mutations 1085

Tab

le2.

cont

inue

d

Prob

and

sN

ucle

otid

eC

hang

ePr

otei

nC

hang

eE

xon

(Int

ron)

Ref

eren

cePr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Mut

atio

nIn

heri

tanc

e

62c.

758A3

Cp.

Gln

253P

ro3

(3)

Bila

tera

lM

CD

TO

Pcy

sts

inm

othe

r(G

FR62

at25

year

s)an

dgr

and

mot

her

Mut

atio

nin

the

mot

her

63c.

717d

elG

p.Se

r242

fs3

Thi

s stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Hyp

erec

hoge

nic

kid

neys

,co

rtic

alm

icro

cyst

s,no

rmal

GFR

at1.

5ye

ars;

fath

erw

ith

rena

lcy

sts

and

dia

bete

s

Mut

atio

nin

the

fath

er

64c.

766C3

Tp.

Pro2

56Se

r3

Thi

s stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lco

rtic

alcy

sts,

norm

al-s

ized

kid

neys

,no

rmal

GFR

at8

year

s;ph

enot

ype

inth

efa

ther

unkn

own

Mut

atio

nin

the

fath

er

65IV

S380

9�

1G3

A(3

)T

his stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys,b

ilate

ral

cyst

s

Bila

tera

lco

rtic

alcy

sts,

unila

tera

lU

PJ,n

eona

tal

rena

lfa

ilure

,nor

mal

GFR

at3

year

s;fa

mily

hist

ory

ofd

iabe

tes;

phen

otyp

ein

the

fath

erun

know

n

Mut

atio

nin

the

fath

er

66c.

840d

elC

p.Pr

o280

fs4

Thi

s stud

yE

nlar

ged

kid

neys

,lar

gecy

sts,

pyel

icd

ilati

on,

dup

licit

y,pa

ncre

ashy

popl

asia

TO

PN

D

67c.

854G3

Ap.

Gly

285A

sp(1

7)B

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lhy

pere

chog

enic

kid

neys

�un

ilate

ral

cort

ical

mic

rocy

sts,

norm

alG

FRat

3ye

ars;

mot

her

wit

hre

nal

cyst

s,G

FR55

at35

year

s

Mut

atio

nin

the

mot

her

68c.

883C3

Tp.

Arg

295C

ys4

(17)

ND

Smal

lan

dcy

stic

kid

neys

(unk

now

nG

FR);

mot

her

wit

hre

nal

cyst

san

dC

RF

(pre

cise

GFR

unkn

own)

Mut

atio

nin

the

mot

her

69c.

883C3

Tp.

Arg

295C

ys4

Bila

tera

lhy

pere

chog

enic

kid

neys

,bila

tera

lco

rtic

alcy

sts

Cor

tica

lcy

sts,

hype

ruri

cem

ia,n

eona

tal

rena

lfa

ilure

,nor

mal

GFR

at8

year

s

De

novo

1086 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010

Tab

le2.

cont

inue

d

Prob

and

sN

ucle

otid

eC

hang

ePr

otei

nC

hang

eE

xon

(Int

ron)

Ref

eren

cePr

enat

alR

enal

Phen

otyp

ePo

stna

tal

Ren

alPh

enot

ype

Mut

atio

nIn

heri

tanc

e

70c.

895T3

GpT

rp29

9Gly

4T

his stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys,b

ilate

ral

cort

ical

mic

rocy

sts

Bila

tera

lhy

pere

chog

enic

kid

neys

,cor

tica

lm

icro

cyst

sC

RF

(GFR

51at

3ye

ars)

ND

71c.

766C3

Tp.

Asn

302L

ys4

Thi

s stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lco

rtic

alcy

sts,

CR

F(G

FR60

at7

year

s)N

D

72E

xon

4d

elet

ion

c.81

0_10

45d

el23

6p.

Arg

270f

s4

(3,1

3)U

nila

tera

lM

CD

Abs

ence

ofhy

pert

roph

yof

the

cont

rala

tera

lki

dne

y,V

UR

,CR

F(G

FR65

at4

year

s)

De

novo

73c.

1136

C3

Ap.

Ser3

79X

5T

his stud

yN

DH

yper

echo

geni

cki

dne

ys,

cort

ical

mic

rocy

sts,

CR

F(G

FR61

at15

year

s),

did

elph

icut

erus

�pa

ncre

atic

hypo

plas

ia

De

novo

74c.

1360

C3

Tp.

Gln

454X

7T

his stud

yU

nila

tera

lM

CD

,oth

erki

dne

yhy

pere

chog

enic

Uni

late

ral

MC

D,o

ther

kid

ney

hype

rech

ogen

icw

ith

cort

ical

mic

rocy

sts,

norm

alG

FRat

2ye

ars

De

novo

75c.

del

AG

1363

–136

4p.

Ser4

55fs

7T

his stud

yB

ilate

ral

hype

rech

ogen

icki

dne

ys

Bila

tera

lco

rtic

alcy

sts,

left

hypo

plas

tic

kid

ney

CR

F(G

FR80

at14

year

s)

ND

CR

F,ch

roni

cre

nal

failu

re;E

SRF,

end

-sta

gere

nal

failu

re;U

PJ,u

rete

rope

lvic

junc

tion

.

Clin J Am Soc Nephrol 5: 1079–1090, 2010 Renal Phenotypes and HNF1B Mutations 1087

isolated bilateral hyperechogenic fetal kidneys with normal orslightly enlarged (��3 SD) size were the most frequent phe-notype observed before birth in patients who carried an HNF1Bmutation (3); however, one limit of our study is that our pop-ulation represents patients who had congenital anomalies ofthe kidney and urinary tract and whose samples were receivedfor HNF1B testing in France during a certain period of time.Thus, it will be of interest to perform a prospective study that

includes all hyperechogenickidneys with normal or slightlyenlarged size diagnosed beforebirth and test them for HNF1Bmutation. Almost all patientswith HNF1B mutation andmoderately enlarged hypere-chogenic kidneys before birthdisplayed normal-sized or smallkidneys with hyperechogenic-ity and/or cortical cysts in thepostnatal period, suggesting aslow-down in kidney growthafter birth.

Besides hyperechogenic kid-neys, HNF1B mutations wereassociated with several otherprenatal renal abnormalitiesbut far less frequently: bilateralor unilateral MCD, unilateralrenal agenesis, kidney hypopla-sia, isolated pyelic dilation, orkidneys with individualizedcysts. Because unilateral renalagenesis has been reported inassociation with HNF1B abnor-malities only in adults so far (5),it had been suggested that these

cases may be due to involution of overlooked MCD (13). Ourstudy shows that genuine renal unilateral agenesis can be as-sociated with HNF1B mutation. The absence of cases of bilateralagenesis may be due to the small number of patients tested. Inall cases of renal unilateral agenesis associated with HNF1Bmutation, the single kidney was abnormal. More generally,except for one patient with unilateral hypoplasia and normalcontralateral kidney, all probands who carried HNF1B muta-tion displayed bilateral kidney abnormalities. Regarding extra-renal symptoms, no patient with HNF1B mutation developeddiabetes during early childhood. Only four presented diabetesat 17, 20, 31, and 42 years, respectively, and one developedgestational diabetes. Six other probands had family history ofdiabetes, but the type of diabetes in relatives was not alwaysknown.

Twelve patients with HNF1B mutation had early goutand/or hyperuricemia, a feature that has been reported inpatients with HNF1B mutations (15), but this frequency must beunderestimated because the uricemia dosage was not availablefor many patients in our cohort. Only one adult proband whopresented with tubulointerstitial nephropathy and early hyper-uricemia that was previously shown not to be associated withUMOD mutation was carrying an HNF1B mutation. The asso-ciation of familial hyperuricemic nephropathy with HNF1Bmutation has been reported previously (5,15), but the mecha-nisms responsible for the reduced fractional excretion of uricacid are not well understood. HNF1�/HNF1� heterodimershave been shown to bind and positively regulate the proximalpromoter region of SLC22A12, encoding a transporter that is

Figure 1. HNF1� protein and localization of the various mutations identified in this study.The N-terminal portion of the protein consists of a short dimerization domain (dim). TheDNA-binding domain is characterized by a region distantly related to the POU box-specificdomain and an atypical homeodomain structure. The residues required for HNF1� trans-activation have been mapped to the carboxy-terminal region. Deletions are indicated by asolid line. *Novel mutation.

Figure 2. Type of HNF1B mutation (�, deletion of the entiregene; u, missense mutations; f, truncating mutations) accord-ing to the renal phenotype in patients and affected relatives. 1,prenatal hyperechogenic kidneys; 2, hyperechogenic kidneydiagnosed after birth; 3, MCD; 4, unilateral renal agenesis; 5,cystic disease; 6, renal hypoplasia; 7, tubulointerstitial nephri-tis; 8, pyeloureteral junction; 9, pelvic kidney; 10, lack of renalanomaly.

1088 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010

responsible for the resorption of urate in the apical membraneof the renal proximal tubule (16); therefore, loss of functionwould be expected to lead to hypouricemia. The overlap be-tween phenotypes associated with HNF1B loss of function andfamilial UMOD hyperuricemic nephropathy may not seem sur-prising, because UMOD was shown to be a target of HNF1�

(10); however, familial hyperuricemic nephropathy associatedwith UMOD mutations is thought to be due to a defect inuromodulin transport, associated with a dominant effect, ratherthan to haploinsufficiency. Thus, the development of the samephenotype associated with HNF1B haploinsufficiency is notfully understood. Nevertheless, the finding of hyperuricemiaand/or of low uric acid excretion fraction should be an addi-tional argument to screen for HNF1B mutation in patients whopresent with congenital anomalies of the kidney and urinarytract.

Hypomagnesemia was also found in several individuals withHNF1B mutation, although blood magnesium dosage was notalways performed. Low plasma magnesium level was recentlyreported by another group and may be related to the transcrip-tional regulation of FXYD2 by HNF1� (6). In addition to thefrequent and moderate elevation of liver enzymes that waspreviously reported (17), we observed a severe cholestasis withpruritus in the affected mother of one patient. Cholestasis as-sociated with HNF1B mutation was previously reported (18)and is not unexpected given the known role of HNF1� in bileduct morphogenesis (19).

Both the type and the severity of the renal disease werevariable in this series, and our data show that HNF1B mutationscan be associated with very severe prenatal renal failure (infour probands, the pregnancy was terminated because of ana-mnios, and termination of previous pregnancy for severe renaldisease with anamnios was reported in relatives in two addi-tional families) as well as with normal renal function in adult-hood. In our series, as in others, there was no obvious correla-tion between the type of mutation and the type and/or severity

of renal disease. We observed both inter- and intrafamilialvariability of the phenotype in patients who harbored the samemutation. The lack of genotype–phenotype correlation and thewide variability observed within a given family make the ge-netic counseling particularly difficult in these families.

AcknowledgmentsWe thank the patients and their family for participation. We are

grateful to the following physicians for contribution of material andclinical data from patients: Dr. Corinne Antoine (Assistance Publique–Hopitaux de Paris, Hopital Saint Louis, Paris, France); Dr. DanielleBruno (Hopital de la Timone, Marseille, France); Dr. Renato Demontis(Centre Hospitalier Laennec, Creil, France); Dr. Philippe Eckart (CentreHospitalier Regional Universitaire de Caen, Caen France); Dr. JeromeHarambat (Centre Hospitalier Regional Universitaire de Bordeaux, Bor-deaux, France); Dr. Anne Maisin (Assistance Publique–Hopitaux deParis, Hopital Robert Debre, Paris, France); Dr. Jelena Martinovic (As-sistance Publique–Hopitaux de Paris, Hopital Necker, Paris, France);Dr. Hubert Nivet (Centre Hospitalier Regional Universitaire de Tours,Tours, France); Dr. Francois Nobili (Centre Hospitalier Regional Uni-versitaire de Besancon, Besancon, France); Dr. Jean Bernard Palcoux(Hopital Hotel Dieu, Clermont Ferrand, France); Dr. Christine Pietre-ment (Centre Hospitalier Regional Universitaire de Reims, Reims,France); Dr. Natacha Raynaud (Centre Hospitalier Felix Guyon, LaReunion, France); and Dr. Christel Thauvin (Hopital d’Enfants, Dijon,France). We are grateful to Nicolas Chassaing and Cathie Prouheze(Service de Genetique, Hopital Purpan, Toulouse, France) for help withmolecular analysis. We thank Mario Tosi (INSERM U614, Rouen Uni-versity Hospital, Rouen, France) for help with quantitative multiplexPCR amplification of short fluorescence fragments.

DisclosuresNone.

References1. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y,

Cockburn BN, Lindner T, Yamagata K, Ogata M, To-monaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI:Mutation in hepatocyte nuclear factor-1 beta gene (HNF1B)associated with MODY. Nat Genet 17: 384–385, 1997

2. Zaffanello M, Brugnara M, Franchini M, Fanos V: HNF1Bgene mutation leads to nephro-urological defects of un-equal severity: an open question. Med Sci Monit 14: RA78–RA86, 2008

3. Decramer S, Parant O, Beaufils S, Clauin S, Guillou C,Kessler S, Aziza J, Bandin F, Schanstra JP, Bellanne-Chan-telot C: Anomalies of the HNF1B gene are the main causeof fetal bilateral hyperechogenic kidneys. J Am Soc Nephrol18: 923–933, 2007

4. Haumaitre C, Fabre M, Cormier S, Baumann C, DelezoideAL, Cereghini S: Severe pancreas hypoplasia and multicys-tic renal dysplasia in two human foetuses carrying novelHNF1beta/MODY5 mutations. Hum Mol Genet 15: 2363–2375, 2006

5. Edghill EL, Bingham C, Ellard S, Hattersley AT: Mutationsin hepatocyte nuclear factor-1beta and their related pheno-types. J Med Genet 43: 84–90, 2006

6. Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LA,Long DA, Hennekam RC, Ledermann SE, Rees L, van’ HoffW, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Can-

Figure 3. Type of HNF1B mutation (deletion, missense muta-tions, truncating mutations) according to the GFR at last fol-low-up (f, GFR �80 ml/min per 1.73 m2; �, GFR �80 ml/minper 1.73 m2) and age at last follow-up (p).

Clin J Am Soc Nephrol 5: 1079–1090, 2010 Renal Phenotypes and HNF1B Mutations 1089

sick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL,Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D:HNF1B mutations associate with hypomagnesemia andrenal magnesium wasting. J Am Soc Nephrol 20: 1123–1131,2009

7. Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Ce-reghini S: Variant hepatocyte nuclear factor 1 is requiredfor visceral endoderm specification. Development 26: 4795–4805, 1999

8. Reber M, Cereghini S: Variant hepatocyte nuclear factor 1 ex-pression in the mouse genital tract. Mech Dev 100: 75–78, 2001

9. Coffinier C, Barra J, Babinet C, Yaniv M: Expression of thevHNF1/HNF1beta homeoprotein gene during mouse or-ganogenesis. Mech Dev 89: 211–213, 1999

10. Gresh L, Fischer E, Reimann A, Tanguy M, Garbay S, ShaoX, Hiesberger T, Fiette L, Igarashi P, Yaniv M, Pontoglio M:A transcriptional network in polycystic kidney disease.EMBO J 23: 1657–1668, 2004

11. Gong Y, Ma Z, Patel V, Fischer E, Hiesberger T, PontoglioM, Igarashi P: HNF-1beta regulates transcription of thePKD modifier gene Kif12. J Am Soc Nephrol 20: 41–47, 2009

12. Charbonnier F, Raux G, Wang Q: Detection of exon dele-tions and duplications of the mismatch repair genes inhereditary nonpolyposis colorectal cancer families usingmultiplex polymerase chain reaction of short fluorescentfragments. Cancer Res 60: 2760–2763, 2000

13. Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S,Morin D, Clauin S, Deschenes G, Bouissou F, Bensman A,Bellanne-Chantelot C: Renal phenotypes related to hepa-tocyte nuclear factor-1beta (HNF1B) mutations in a pedi-atric cohort. J Am Soc Nephrol 17: 497–503, 2006

14. Sunyaev S, Ramensky V, Koch I, Lathe W 3rd, KondrashovAS, Bork P: Prediction of deleterious human alleles. HumMol Genet 10: 591–597, 2001

15. Bingham C, Ellard S, van’t Hoff WG, Simmonds HA, Mari-naki AM, Badman MK, Winocour PH, Stride A, LockwoodCR, Nicholls AJ, Owen KR, Spyer G, Pearson ER, Hatter-sley AT: Atypical familial juvenile hyperuricaemic ne-phropathy associated with a hepatocyte nuclear factor-1beta gene mutation. Kidney Int 63: 1645–1651, 2003

16. Kikuchi R, Kusuhara H, Hattori N, Kim I, Shiota K, Gonza-lez FJ, Sugiyama Y: Regulation of tissue-specific expressionof the human and mouse urate transporter 1 gene byhepatocyte nuclear factor 1 alpha/beta and DNA methyl-ation. Mol Pharmacol 72: 1619–1625, 2007

17. Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P,Daumont M, Douillard C, Dubois-Laforgue D, DusselierL, Gautier JF, Jadoul M, Laloi-Michelin M, Jacquesson L,Larger E, Louis J, Nicolino M, Subra JF, Wilhem JM,Young J, Velho G, Timsit J: Large genomic rearrange-ments in the hepatocyte nuclear factor-1beta (HNF1B)gene are the most frequent cause of maturity-onsetdiabetes of the young type 5. Diabetes 54: 3126 –3132,2005

18. Beckers D, Bellanne-Chantelot C, Maes M: Neonatal cho-lestatic jaundice as the first symptom of a mutation in thehepatocyte nuclear factor-1beta gene (HNF-1beta). J Pediatr150: 313–314, 2007

19. Coffinier C, Gresh L, Fiette L, Tronche F, Schutz G, BabinetC, Pontoglio M, Yaniv M, Barra J: Bile system morphogen-esis defects and liver dysfunction upon targeted deletion ofHNF1beta. Development 129: 1829–1838, 2002

20. Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C,Noel LH, Velho G, Timsit J: Clinical spectrum associatedwith hepatocyte nuclear factor-1beta mutations. Ann InternMed 140: 510–517, 2004

Access to UpToDate on-line is available for additional clinical informationat http://www.cjasn.org/

1090 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 5: 1079–1090, 2010