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D G Bichet Familial nephrogenic diabetes 183:2 R29–R40 Review insipidus

GENETICS IN ENDOCRINOLOGY Pathophysiology, diagnosis and treatment of familial nephrogenic

Correspondence Daniel G Bichet should be addressed Departments of Medicine, and Physiology, University of Montreal and Service, Research to D G Bichet Center, Hôpital du Sacré-Coeur de Montreal, Montreal, Quebec, Canada Email [email protected]

Abstract

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine- (AVP) is normally produced but not recognized by the with an inability to concentrate urine despite elevated plasma concentrations of AVP. with hyposthenuria and are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter’s syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter’s syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration European Journal of Endocrinology episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.

European Journal of Endocrinology (2020) 183, R29–R40

Invited Author’s profile Daniel G Bichet, MD is Professor of Medicine, Pharmacology and Physiology at the Université de Montréal and a staff nephrologist at the Hôpital du Sacré-Coeur de Montréal. In collaboration with Mariel Birnbaumer (Baylor) his laboratory identified the first mutations responsible for X-linked nephrogenic diabetes insipidus. Dr. Bichet obtained a Canadian Institute Health Research Chair in Genetics of Renal Diseases from 2003 to 2010. His laboratory is contributing to the prevention of extreme dehydration states in children with polyuric disorders. Dr. Bichet received the Medal of the Kidney Foundation of Canada in 1998, a Doctorat Honoris Causa from the University of Nancy (France) in 1999 and the Jean Hamburger Medal in 2010.

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-20-0114 European Journal of Endocrinology https://eje.bioscientifica.com collecting ductcellsandisdiffuselydistributed medullary ducts. Itisexclusivelypresent inprincipalcellsofinner vasopressin-regulated water channelinrenalcollecting proteins thatfacilitatewater transport( are membersofasuperfamily ofintegralmembrane permeability ofthatmembrane.Thesewaterchannels into theluminalmembrane,therebyincreasingwater insertion ofaspecificwaterchannel,aquaporin-2(AQP2), final stepin theantidiuretic action of AVP isthe exocytic the basolateralmembraneofcollectingductcells.The the vasopressin V2 receptor (AVPR2) ( activates theprocessofwaterreabsorptionbybinding to proteins. AVP, ( secreted from the Water homeostasisinthekidneyisregulatedby threekey The AVP-AVPR2-AQP2shuttlepathway antidiuresis (NSIAD) nephrogenic syndromeofinappropriate loss-of-function (NDI)andgain-of-function,the AVPR2 isaG-protein-coupledreceptor(GPCR)with excreted ( If nowaterchannelsarepresentdiluteurinewillbe concentration gradientandtheurineisconcentrated. present, waterexitsthetubulefollowinginterstitial the availabilityofwaterchannels.Ifthesechannelsare The finalosmolalityoftheurineissolelydependenton urine osmolalityistypicallyaround50–100mosmol/kg. the AVP-sensitive connectingtubulesandcollectingducts, into transporting onesodiumandchloride).Atentry as Na via SLC12A3 (also known for counter-currentconcentration( isotonic whenitenterstheloopofHenle,keysegment the osmoticgradient.Theremainingurineisthusstill in the proximal tubule, water follows passively along (AQP1) waterchannels( owing totheconstitutiveexpressionofaquaporin-1 the proximal tubule, which is freely permeable to water daybyhealthykidneys. produced every glomerularfiltrateis Approximately 180Lofprimary water channel vasopressin V2receptorandtheaquaporin collecting duct:twocriticalproteins:the Water reabsorptioninprincipalcellsofthe familial NDI Pathophysiology andetiologiesof Review Further removal of sodium chloride occurs in the The vastmajorityofthisfiltrateisreabsorbed in + -Cl Fig. 2 − cotransporter, NCC, inhibited, ). 1 ). Assolutesarereabsorbed D GBichet Fig. 1 Fig. 2 3 ). , 4 ). AQP2isthe ) located on 2 ),

NDI anagonistforthevasopressin V2receptor(AVPR2), (SIADH) ( mimicking thesyndrome of inappropriateantidiuresis isatypical manifestationofNSIAD, NDI areatriskofhypernatremic dehydration,whereas or absenceofvasopressin.Consequently, patients with dilutionisimpaired,independentofthe presence urinary kidneys cannotconcentratetheurine,whereasinNSIAD R137C, R137L, F229V, I130N ( identified AVPR2 gain-of-functionmutations( (NSIAD). NDIisthemirrorimageofNSIADwithfour nephrogenic syndromeofinappropriateantidiuresis exceptions includingX-linkedNDIandthe diseases areautosomalrecessive( encoding aG-protein-coupledreceptor;thus,mostsuch generally requires loss of function of both alleles of a gene Clinically significantimpairmentofsignaltransduction Loss offunctionorgainAVPR2 sodium (PNa). of theapicalmembranetowater(Pf),urea(PUrea),and ducts leadstoselectiveincreasesinthepermeabilities AVP stimulationoftheprincipalcellscollecting ofwaterdiuresis.Incontrast, formed duringintervals permit the excretion of large volumes of hypotonic urine urea, andwater. Thesespecializedpermeabilityproperties low permeabilities to sodium, duct epithelia exhibit very summary, intheabsenceofAVP stimulation,collecting in the inner medullary collectingduct,predominantlyin in theinnermedullary regulating the urea transporter UT-A1, which is expressed increases thewaterreabsorptivecapacityofkidneyby collectingducts.Inaddition,vasopressin renal medullary AQP4 arethewaterchannelsinbasolateralmembranesof increased transcriptionofthe channels. Thisincreaseisthoughttobeaconsequenceof for 24hormore,AVP increasestheabundance of water which requiresasustainedelevationofcirculating AVP the luminalmembrane,andinlong-termregulation, the movementofAQP2 from the intracellular vesicles to hypothesis) ( vesicles intotheapicalplasmamembrane(theshuttle insertion ofpreformedwaterchannelsfromintracellular arethoughttorepresenttheexocytic observations condition oraftervasopressinadministration.These apical staining of AQP2 is intensified in the dehydrated in thecytoplasmeuhydratedcondition,whereas of principalcollectingductcellstosodium( its terminal part ( insipidus Familial nephrogenicdiabetes The short-termregulationofAQP2byAVP involves 12 ). Thediagnosticpathways alsomirror:In Fig. 2 6 ). ). AVP also increases the permeability Downloaded fromBioscientifica.com at09/27/202102:36:38PM AQP2 9 8 , ), butthereareseveral 10 gene( 183 , 11 :2 ). In NDI, the 5 ). AQP3and Fig. 3 7 R30 ). In via freeaccess ):

European Journal of Endocrinology capacity in patients suspected of NSIAD. In patients who dilution as tolvaptanprovidesanassessment ofurinary Conversely, administration ofanAVPR2 antagonist,such to assesstheabilityofkidneys toconcentrateurine. such asd-aminoD-argininevasopressin(dDAVP), isgiven of sodiumchloride(inshort-loopednephrons),completingthe counter-currentmultiplier. generates thedrivingforceforremovalofwaterfrom thindescendinglimb(TDL)(inlong-loopednephrons)andtheentry increasing boththeexpressionofNKCC2andsodiumco-transporter NCC( associated withvariablesolutes(videinfra).TheMAGED2protein isexpressedintheTALanddistalconvolutedtubule Loss-of-function of NKCC2, ROMK or ClCKb or Barttinwill be responsible for Bartter’ssyndromefromtype 1 to 4 with loss of water Na-K-ATPase andchloridereturnstotheinterstitialfluidthrough thechloridechannelsCLC-Kaand-Kb(rightpartofFig.1). recycles morethan90%ofthereabsorbedpotassiuminlumen, whilesodiumisreabsorbedattheluminalmembraneby This NKCC2co-transporterisresponsiblefor10–25%ofthetotal sodiumreabsorptionofthenephronandaROMKchannel potassium andtwochlorides,hencetheabbreviationNKCC2(oneofCisforCo-transport),inhibitedbyfurosemide ( removes sodiumchlorideviaNKCC2,therebydilutingtheurine.Thiselectroneutralproteinco-transportsonesodium, known asthedilutingsegment),whichisimpermeabletowater,duelackofexpressionanyaquaporin,butactively in whichthesteepestpartofosmoticgradientisgenerated( the medullaryinterstitium.Aqp1expressionismainlyrestrictedtofirst60%ofTDLratherthandeeperpapillary parts concentration beginsinthethindescendinglimb(TDL).MechanismsofincludeAQP1-mediatedexitwater into availability ofaquaporin2waterchannels.Theosmolalitiesthetubularfluidandinterstitialareindicated.Urine involves passivewatereffluxand/orNaClinflux.Finalconcentrationofurineoccursinthecollectingductanddepends onthe chloride co-transporter).Themechanismofconcentrationinthethindescendinglimbisnotcompletelyresolved,butlikely thick ascendinglimbbythetransportersolutecarrierfamily12member1(SLC12A1,alsoknownasNKCC2,asodium,potassium, the collectingduct.TheconcentrationgradientgeneratedinloopofHenleisdrivenbyactivereabsorptionNaCl inthe multiplier systemthatconcentratestheurine.UrineisisotonicwhenitentersloopofHenleandhypotonicexits into Schematic representationoftherenalconcentrationanddilutionmechanisms.TheloopHenleformsacounter-current Figure 1 Review D GBichet 57 ). Urinesubsequentlyentersthethickascendinglimb(TAL,also levels, measuredeither directly orindirectlyvia the kidneys for an appropriate response. Lastly, vasopressin water deprivation(NDI)or load(NSIAD)challenges concentration,a having anunderlyingdefect inurinary did notpresentwithdysnatremia,yet,aresuspected of insipidus Familial nephrogenicdiabetes 59 ). Theaccumulationofsolutesintheinterstitium Downloaded fromBioscientifica.com at09/27/202102:36:38PM https://eje.bioscientifica.com 183 :2 58 R31 ). via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com stimulation ofAQP2expression throughthefrizzledd8- stimulation ofadenylcyclaseby the permeability ofthismembrane.Microtubulesandactinfilaments arenecessaryforvesiclemovementtowardthemembrane.The on inthediscussionof the waterchannelproteins(representedashomotetrameric complexes, seeassemblyofAQP2homtetramericcomplexesfurther responsive element-binding protein (CREB), which stimulates transcription from the AQP2 promoter. Cytoplasmic vesicles carrying target ofthegeneratedcAMP.Onlongterm,vasopressin alsoincreasesAQP2expressionviaphosphorylationofthecAMP the adenylylcyclasecatalyst.ProteinkinaseA(PKA)andpossibly theexchangefactordirectlyactivatedbycAMP(EPAC)are Generation ofcAMPfollowsreceptor-linkedactivationthe heteromeric G-protein(G hydrophobic transmembranedomainsseparatedbyalargecytoplasmic loopandterminatesinalargeintracellulartail. cyclic adenosinemonophosphate(cAMP).Thetopologyofadenylyl cyclaseischaracterizedbytwotandemrepeatsofsix to generatesmall-moleculesecondmessengers.AVPactivates adenylylcyclase6increasingtheintracellularconcentrationof with theligand-boundreceptor,andaneffector(inthiscase,adenylylcyclase6)thatinteractsdissociatedG-protein subunits extracellular milieu,aG-proteinthatdissociatesintoalphasubunitboundtoGTPandbetagammasubunitsafterinteraction G-protein-coupled receptorsignalingconsistsofthreesteps:ahepta-helicalthatdetectsligand(inthiscase,AVP) inthe duct. AVPisboundtotheV Schematic representation of the effect of arginine vasopressinto increasewaterpermeability in the principal cellsof the collecting Figure 2 Review AQP2 2 receptor,AVPR2(aG-protein-linkedreceptor) onthe basolateralmembrane. Thebasicprocessof mutants)arefusedtotheluminalmembraneinresponse AVP,therebyincreasingthewater D GBichet β -3 adrenergicreceptorandother GPCRsknowntobeexpressedinprincipalcellsandthe β -catenin pathwayarealsorepresented. insipidus Familial nephrogenicdiabetes s ) andinter-actionofthefreeG Downloaded fromBioscientifica.com at09/27/202102:36:38PM 183 :2 as -chain with R32 via freeaccess European Journal of Endocrinology levels and a history ofspontaneouslylowfluidintake. levels andahistory elevated urineosmolalitydespite suppressedvasopressin were normonatremicwhen investigated,buttheyhad levels. Otherpatientshad no apparentsymptomsand elevated urineosmolality, andsuppressedvasopressin associated witheuvolemichyponatremia,inappropriately some patientspresentedwithseizuresinearlychildhood the dominantlyinheritedmutationswasquitevariable: ( (LHGR) andparathyroidhormone(PTH1R)receptors of AVPR2 butalsoofotherGPCRs,includingthelutropin clinical symptoms,suggestinggainoffunctionnotonly with hyponatremia,anditwasassociatedadditional mutation p.F376Vwasreportedintwounrelatedpatients the GNASvariants p.F68_G70 del and p.M255V. The Gas dominantly inheritedformofNSIADsegregatingwith NSIAD. Miyado Gs alpha-protein GNAS as another cause of stimulatory Two recentstudieshaveidentifiedmutationsinthe syndrome ofinappropriateantidiuresis alpha-coding GNASgeneidentifiedinnephrogenic Germline-derived gain-of-functionvariantsofGs vasopressin secretion( concentrationfromthoseofdisturbed of urinary copeptin ( 15 Review ). Theseverityofthephenotypeinpatientswith 13 ), canhelpdistinguishnephrogenicdisorders t al et . ( 13 14 ). ) reported two families with a D GBichet only 9of82patients(11%) had normalintelligence( prevalent intheCrawfordand Bodestudy, whichfoundthat a consequenceofrepeated episodes ofdehydration,was dehydration hypernatremic episodes.Mentalretardation, two observed of skewedXchromosomeinactivationandwehave variable degrees of polyuria and polydipsia because treatment. Heterozygousfemalepatientsmayexhibit ‘historical’ consequencesofalatediagnosisandlack of physical retardationandrenalfailurearetheclassic to thebrain,kidneys,andotherorgans.Mental that isnotsufficienttosustainadequateoxygenation severe thattheylowerarterialbloodpressuretoadegree Dehydration episodes can beso personal observations). onthefirstday oflife(DGB osmolality couldbeobserved of life.Hypernatremiawithaninappropriatelylowurine hypernatremia, and hyperthermia as early as the first week a phenotypecharacterizedbyearlydehydrationepisodes, receptor ( result inalossoffunctionordysregulationtheV2 to X-linked NDIissecondary NDI (OMIM#304800) Clinical presentationandhistoryofX-linked restriction withnormalizationofhyponatremia. Symptomatic familymembersweretreatedwithfluid insipidus Familial nephrogenicdiabetes 16 ). Malepatientsbearing AVPR2 one complexmutation.Thefivegain-of- site, and22largedeletionmutations, in-frame deletionorinsertion,4splice- frameshift deletionorinsertion,7 There are95missense,18nonsense,46 mutations arenotindicatedonthefigure. affecting thesamecodon;othertypesof different mutationonthecDNAlevel number (withinatriangle)indicates with amissenseornonsensemutation; codes. Asolidsymbolindicatesacodon are shownastheirone-letteraminoacid AVPR2 AVPR2 putative disease-causingloss-of-function receptor (AVPR2)andidentificationof193 Schematic representationoftheV2 Figure 3 R137L, F229V,I130N. function AVPR2mutationsareR137C, heterozygous females withsevere mutations.Predictedaminoacids mutationsand5gain-of-function Downloaded fromBioscientifica.com at09/27/202102:36:38PM AVPR2 https://eje.bioscientifica.com AVPR2 183 mutations,which :2 mutationhave R33 17 via freeaccess ).

European Journal of Endocrinology https://eje.bioscientifica.com first decadeoflifeandcould betheresultofepisodes Chronic renalinsufficiency mayoccurbytheendof in patientswithneurogenic diabetesinsipidus( polydipsiaand tract isalsoseeninpatients withprimary volume ofurineproduced. Dilation ofthelowerurinary tothelarge dilation andobstruction,probablysecondary tract Affected childrenfrequentlyhavelowerurinary lead tohypocaloricdwarfismbeginningininfancy. saltandproteinintake, restrictionofdietary voluntary of largequantitieswater, combinedwiththepatient’s is acommonconsequenceoftheseepisodes.Theintake complicated byconvulsionsordeath.Mentalretardation frequent boutsofhypertonicdehydration,sometimes the conditionisrecognizedearly, children experience in warmweatherexaggeratesthesymptoms.Unless of perspiration,increasedwaterlossduringfeveror patients characteristicallyshownovisibleevidence fever, andfailuretogainweight.Eventhoughthe includes persistentconstipation,erraticunexplained fed withwater. givenbythemothersoften Thehistory suck, will vomit milk soon after ingestion unless pre- almostconstantly,irritable, cry andalthougheagerto recognized duringthefirstweekoflife.Theinfantsare be understoodbyadults. life, when the infant’s demand for water is more likely to polydipsic symptomsusuallyappearafterthefirstyearof secrete AVP during severe dehydration, and the polyuro- Patients withadFNDIretainsomelimitedcapacityto neurohypophyseal (adFNDI)(OMIM#192340)( to haveneurohypophysealautosomaldominantfamilial the familyoriginallydescribedbyWeil werelaterfound associated mental retardation ( insipidus withautosomal transmission and withoutany Lacombe andWeil describedafamilialformofdiabetes and AndreoliwasafamilywithX-linkedNDI( described in1892byMcIlraithanddiscussedReeves to malepatients.We thereforeassumethatthefamily occurrence andtheconfinementofmentalretardation characteristics suggestiveofX-linkedNDIarethefamilial pedigree (vide infra) living past 80 years of age. Two and we knowaffected male members of the Hopewell span withnormalphysicalandmentaldevelopment( with anabundantintakeofwaterallowsanormallife have normalintelligence( demonstrated thatthemajorityoftheirpatientswithNDI had mentalretardation( (90% bearingAVPR2 mutations),20patients(14%) Among the143JapanesepatientswithcongenitalNDI Review The first manifestations of X-linked NDIcan be Early recognitionandtreatmentofX-linkedNDI 19 18 ). ). TheNijmegengroup 23 D GBichet ). The descendants of 21 25 , , 22 26 24 20 ). ). ). ) prevalence ismuchhigher. Ourgroupestimatedthe (Canada) ( 8.8 permillionmalelivebirthsintheprovinceofQuebec disease, withanestimatedprevalenceofapproximately for adefectiveV2receptor( in thesepatientswithX-linkedNDIwaslikelytocode of these results, we predicted that the defective gene to halfofthenormalreceptorresponse.Onbasis in obligate carriers of the disease, possibly corresponding with X-linkedNDI( normal subjects,buthadnoeffectin14malepatients caused anincreaseinplasmacAMPconcentrations administration ofdesmopressin,aV2receptoragonist, urological complicationsand6%hadrenalfailure( nephropathy: 43%ofthe173NDIJapanesepatientshad urological complicationsasaresultofflowobstructive to Chronic kidneydiseaselaterinlifeislikelysecondary dehydration withthrombosisoftheglomerulartufts. cannot beupheldinitsoriginally proposedform.However, American X-linkedNDIfamilies, theHopewellhypothesis at 6%. diagnosed, andthecarrierfrequency hasbeenestimated with atotalof2500inhabitants,30patientshavebeen the UlsterScotsresidinginNovaScotia.Intwovillages on thehighprevalenceofNDIamongdescendants of second emigrationwave.Thisassumptionisbasedmainly in NorthAmericaareprogenyoffemalecarriersthe the ‘Hopewellhypothesis’,( settled inColchesterCounty, NovaScotia. Accordingto second emigrationwave,passengersoftheHopewell, in northern Massachusetts in 1718, the members of a families arrivingwiththefirstemigrationwavesettled for theNewWorld intheeighteenthcentury. Although andleftIreland in Irelandtheseventeenthcentury of ScottishPresbyterianswhomigratedtoUlsterprovince ship were members ofthe Ulster Scot clan, descendants which arrived in Halifax, Nova Scotia, in 1761. Aboard the Hopewell family, namedaftertheIrishshipHopewell, domain 7andtheintracellularCOOHterminus( (L312X) predictiveofareceptorthatlackstransmembrane Cannon ( families). This pedigreewasoriginally described by Mormon pedigreewhosemembersresideinUtah(Utah ( ancestry to be58permillionmalelivebirthsbecauseofshared incidence inNovaScotiaandNewBrunswick(Canada) insipidus Familial nephrogenicdiabetes Thirty-one years ago we observed thatthe Thirty-one yearsagoweobserved Given the numerous mutations found in North Given thenumerousmutations foundinNorth The largestknownkindredwithX-linkedNDIisthe An additionalexamplehasbeenidentifiedina 29 29 28 ). The‘Utahmutation’isanonsensemutation ). ). IndefinedregionsofNorthAmerica,the 27 ). Intermediateresponseswereseen Downloaded fromBioscientifica.com at09/27/202102:36:38PM 30 27 ) mostpatientswithNDI ). X-linkedNDIisarare 183 :2 29 18 ). R34 ). via freeaccess European Journal of Endocrinology Y128S, L161P,G201D, T273M, F287L M311V, N317K, folding andkinesis( diseasesresultingfromerrorsinprotein several hereditary therapeutic approachcould be appliedtothetreatmentof acting aspharmacologicchaperones( but also that misfoldedAVPR2 mutantscouldberescued intracellular compartment.Ourgroupalsodemonstrated to thecellmembraneandwereretainedwithin of themutantV2receptorstestedwerenottransported studied withtheuseof frameshift, deletion,andmissensemutations)hasbeen different mutantV2receptors(includingnonsense, found ( the codingregionofrhodopsingenehavebeen mutations (approximately100)spreadthroughout the lightreceptorrhodopsin.Here,too,manydifferent fourth of patients, the disease is caused by mutations in onset autosomaldominantretinitispigmentosa.Inone- are reminiscentofthose obtained frompatientswithlate- and potentialmechanismsofmutagenesis.Thesedata has describedancestralmutations, male patients will be caused by new mutations. Our group genetic equilibrium,one-thirdofnewcasesinaffected mutation ratesareequalinmothersandfathers,then,at a rareX-linkedrecessivediseasedonotreproduceandif alleles occursbymutation. If affectedmale patients with with healthymalepatients,whereasgainofmutant the highermortalityofaffectedmalepatientscompared of mutantallelesfromthepopulationoccursbecause balanced byrecurrentmutations.InX-linkedNDI,loss that inthepastwaslethalformalepatientsand disease areconsistentwithanX-linkedrecessive Americans, andAfricans),thelowfrequencyof found inmanyethnicgroups(whites,Japanese,African Hopewell pedigree( Nova-Scotia beforetheHopewellshipandlinkedto bearing theHopewellmutationanddefinitelyarrivingin Scot immigrants.We foundotherfamiliesfromNova-Scotia North America by Hopewell passengers or by other Ulster not clearwhethertheHopewellmutationwasbroughtto loop. Becausetheoriginalcarriercannotbeidentified,itis domain, andtheNH2-terminalhalfoffirstintracellular the extracellularNH2-terminus,firsttransmembrane predictive ofanextremelytruncatedreceptorconsisting the otherAVPR2 mutation.Itisanullmutation(W71X), mutation (theHopewellmutation)ismorecommonthan among X-linkedNDIpatientsinNorthAmerica,theW71X Review The basisoflossfunctionordysregulation28 The AVPR2 mutations(D85N, V88M,R104C,R106C, 32 in vivo ). bynonpeptidevasopressinantagonists 31 35 ). ThediversityofAVPR2 mutations ). in vitro expressionsystems.Most D GBichet de novo 33 , 34 mutations, mutations, ). Thisnew in vitro

MAGDE2 polyhydramnios duringpregnancysuggestingBartter’s or an autosomaldominantinheritance( except ifthereisfathertosontransmission,suggesting family withNDI,wealwayssequencethe autosomal mutations in q13. Approximately10%ofNDIcasesarecausedby The of AQP2(OMIM#107777) dominant NDIsecondarytolossoffunction autosomal recessiveand Clinical presentationandhistoryof successfully treatedwithdDAVP ( of thesepatientsbearingmutationshavebeen have beenassociatedwithamildphenotypeandsome N317S, N321Y, P322S and the splice mutant c.276A phosphorylation sites. Well-diffractingphosphorylation of the full- crystals and post-translationalmodifications sites,including 45 residueslonginAQP2which allowsAQP2interaction extracellular sideofthechannel. TheC-terminaltailis the aromatic/Arg(ar/R)selectivity filter, islocatedatthe forming aconstriction.Anotherconstriction,known as which lie in the middle of the permeation channel, Asn-Pro-Ala(NPA)two conserved sequencemotifs, to form a homotetramer ( the membrane,fouraquaporinmoleculesareassembled helices surroundanarrowwater-conductingchannel.In including AQP2( but numerousstructuresareavailableforaquaporins Experimental structuresarenotyetavailableforAVPR2 never receiveintravenousisotonicsaline(videinfra). early pregnancyand,likeallthepatientswithNDI,should risk ofhypernatremicdehydrationiftheyvomitduring Adult womenwithrecessivemutationinAQP2arealsoat compared tofemaleheterozygousforan compound-heterozygous foran infemalepatients homozygous or episodes, observed of polyuria, polydipsia, dehydration loss of function ofAVPR2. The difference is the severity of with lossoffunctionAQP2ascomparedtopatients severity ofdehydrationphenotypesissimilarforpatients twodifferentmutations( gene orcarry described ashomozygousforamutationintheAQP2 patients who are affected with congenital NDI have been (8 mutationsreported)( recessive (34 mutations reported)orautosomal dominant deletion havebeenreported,whichareeitherautosomal insipidus Familial nephrogenicdiabetes AQP2 mutations.Forty-eight mutations and alarge geneislocatedonchromosomeregion12q12- 42 , 43 ). ForAQP2,sixtrans-membrane Downloaded fromBioscientifica.com at09/27/202102:36:38PM 40 AQP2 Fig. 4 , 41 . When we receive a new ). Each monomer exhibits ). Bothmaleandfemale https://eje.bioscientifica.com 18 , AQP2 36 183 AQP2 , Fig. 4 37 :2 AVPR2 mutation(s)as AVPR2 , 38 dominant)or ). Theclinical , 39 mutation. genefirst ) ( Fig. 3 R35 > G) G) via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com whereby themutantprotein associateswithfunctional protein andtooperatethrough adominantnegativeeffect be restrictedtothecarboxy-terminal endoftheAQP2 functionality ( resulting mutants partially retaining their water channel assembly areassociated with milder phenotypes, with such as its dimension and composition, or the tetramer However, mutations affectingotherfeaturesofthepore, the ar/Rselectivityfilter–areaffectedisalsocompromised. of mutantswhoseporesignaturemotifs–NPA boxesand retained intheendoplasmicreticulum.Thefunctionality sinceunfolded and therefore osmotic gradient observed, mutants arenon-functionalwithnowaterpassageunder helices packing cause the most severe phenotypes. These the monomerfoldingbyalteringintra-monomer Mutations affecting loss fortheprotein phosphorylation. tetramer assembly, ( identified include theN-andC-terminaltails.Calvanese AQP2 experimentalstructuresaretruncatedanddonot length AQPsaredifficulttoobtain,therefore,theavailable Review Autosomal dominant mutations are believed to AQP2 43 mutationsaffecting( ). 3 ) themonomerfolding,and( D GBichet 1 ) thepore,( et al 4 ) signal 2 . ( ) the 43 ) with polyhydramnios,profound polyuria,hyponatremia, SLC12A1 isosthenuria havebeenfound tobear Patients withpolyhydramnios, hypercalciuria, and losing tubulopathies Polyuria inhereditaryhypokalemicsalt- gastroenteritis ( abnormalities ininfantswithcystinosiswhohaveacute as tocontributedeathfromdehydrationandelectrolyte Polyuria may be as mild as persistent enuresis or as severe dehydration incystinosis Polyuria, polydipsia,electrolyteimbalance,and syndromes Other heriditarypolyuro-polydipsic normal targetingandfunction( AQP2 proteins within intracellular stores, thus preventing insipidus Familial nephrogenicdiabetes (NKCC2)and 45 ). V168M; G175R;G180S;C181W;P185A; 369delC; T125M;T126M;A147T;D150E; Q93X;G100X; G100V;G100R;I107D; G64R; N68S;A70D;V71M;R85X; M1I; L22V;V24A;L28P;G29S;A47V;Q57P; codon (forreferences,seeTable1of( more thanonemutationinthesame triangles areindicatingaminoacidswith indicate thelocationofmutationsand according to Deen cytoplasmic domainsaredefined extracellular, transmembraneand phosphorylation site(Pa)isindicated.The helices. ThelocationofthePKA represented withsixtransmembrane causing AQP2mutations.Amonomeris identification of48putativedisease- A representationoftheAQP2proteinand Figure 4 also indicated). motifs andthe Exon 1;AF147093,Exons2through4.NPA accession numbers–AQP2:AF147092, R254Q; R254L; E258K and P262L. GenBank G215C; S216P;S216F;Asn220Thr;K228E; R187C; R187H;A190T;G196D;W202C; Downloaded fromBioscientifica.com at09/27/202102:36:38PM MAGED2 44 N -glycosylation siteare ). mutations.Patients et al. 183 ( :2 60 KCNJ1 ). Solid symbols

(ROMK), R36 40 via freeaccess ): European Journal of Endocrinology effect mustbeweighedagainst thesideeffectsofthese output.Thisadvantageous kg/day) mayreduceurinary kg/day topreventhypokalemia) orindomethacin(2mg/ usually 25mgbidinyoungadults, withamiloride0.3mg/ sodium diet,theuseofdiuretics (,3mg/kg/day, to ensure normal development. In addition to a low- provided withunrestrictedamountsofwaterfrombirth by anadequatewaterintake.Thus,patientsshouldbe diagnosis ( excess isalsoofimportancefordefinitivemolecular nephronophthisis, andapparentmineralocorticoid with cystinosis,hypokalemicsalt-losingtubulopathy, Mutationalanalysisof polyuric patients observations. few areseverelyaffected( receptor donotpresentwithclinicalsymptoms,anda female patients heterozygous for a mutation in the V2 female carriersinfamilieswithX-linkedNDI.Most also important for the identification of nonobligatory and mentaldevelopmentisnormal.Geneanalysis experienced episodesofdehydration,andtheirphysical low-sodium diet,andhydrochlorothiazide.Theynever were immediatelytreatedwithabundantwaterintake,a normal sequenceonbothalleles.Theaffectedpatients identified mutation,2wereheterozygous,and1hada subjects, 3werefoundtobehomozygousforthepreviously recessive mutantswasdonein4familiesforatotalof6 had normalsequences.DiagnosisofAQP2autosomal patients werefoundtobearmutantsequences;28males in 92ofourpatientsfrom79families.Thirty-ninemale samples ( testing ofculturedamnioticcellsorchorionicvillus Diagnosis ofX-linkedNDIwasaccomplishedbymutation retardation associatedwithepisodesofdehydration. diagnosis andtreatmentcanavertthephysicalmental analysis ( recommend mutationanalysisorcell-freefetalDNA X-linked and autosomal recessivediabetesinsipidus to We familieswith encouragephysicianswhoobserve and treatment Carrier detection,perinataltesting with urea,ahypertonicmilieu( interstitium and thereby generating, together medullary ROMK, NKCC2,andBarttinintransferringNaCltothe studies demonstratethecriticalimportanceofproteins deafness werefoundtobearBSNDmutations.These hypochloremia, metabolicalkalosis,andsensorineural Review All complicationsofcongenitalNDIarepreventable 47 n 49

= , 17) orcordbloodobtainedatbirth( 48 ). ) beforethebirthofaninfantbecauseearly 28 ) andBichet,unpublished 46 D GBichet ) ( Fig. 1 rightpart). n =75)

for thetimeperiod2,3and4. the increaseinurineosmolality from100to150mosmol/kg Eq/24 hoursonday1and50mEq/24 honday2.Pleasenote discontinued during2dayswith asodiumintakeof100m sodium intakeof9mEq/24h;(5) hydrochlorothiazide 94) hydrochlorothiazidediscontinuedduring4dayswitha every 8hduring4dayswithasodiumintakeof9mEq/24h; sodium intakeof50mEq/24h;(3)hydrochlorothiazide25mg hydrochlorothiazide 25mgevery8hduring6dayswitha during 3dayswithasodiumintakeof50mEq/24h;(2) studied byEarleyandOrloff( patient SZwithX-linkednephrogenicdiabetesinsipidus recovery fromantidiuresisinducedbyhydrochlorothiazidein Graphical representationoftheeffectsodiumintakeon Figure 5 NDI, thereisamaximallowurineosmolalitydetermined to thecollectingductandlostinurine.Inhereditary of theglomerularfiltrate,sothatlesswaterispresented volume withsubsequentenhancedproximalreabsorption tubule. The loss of sodium leads to a reduction in plasma of thiazide-sensitiveco-transporterSLC12A3inthedistal from mild sodium depletion induced by the inhibition in urine volume ( anincreaseinurineosmolalityandadecrease observed years ofagewithNDIlikelybearing with a low sodium diet to four male patients from 7–17 osmolality( urinary volumeaswellanincreased diminution inurinary nephrogenic diabetesinsipidus,resultsinastriking or diabetes insipidus,andtopatientswithpituitary administration ofthiazidetoanimalswithpituitary thatthechronic Crawford andKennedyobserved reduction oftheGFRandgastrointestinalsymptoms). drugs (thiazides:electrolytedisturbances;indomethacin: proximal reabsorption, hence, an increased inurine and theurinevolumewillbelessdilutedbyanincrease by the loss of AVPR2 function and the urine osmotic load insipidus Familial nephrogenicdiabetes Fig. 5 50 ). EarleyandOrloffgavethiazides Downloaded fromBioscientifica.com at09/27/202102:36:38PM ) ( 51 51 ). (1):controlmeasurements ). The antidiuresis results https://eje.bioscientifica.com AVPR2 183 :2 mutationsand R37 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com mutation analysis( nephrogenic DI ismadeandDNAshould be obtained for more than100mosmol/kgover baseline,thediagnosisof next 2h.Iftheurineosmolality doesnotincreaseby overthe osmolality atbaselineand at 30-minintervals 0.4 µg/kgofbodyweight)withmeasurementtheurine or intravenouslyinfusedover20min,maximumdose the administrationofdesmopressin(1µgsubcutaneously unclear insuchpatients,thepreferreddiagnostictest is urine osmolality plasma sodium145mEq/Lorhigherwithaconcomitant nephrogenicDI(e.g.documented to havehereditary young infants suspected performed innewbornsorvery todehydration. Watersecondary restriction is not hypernatremia could occur with intracerebral bleeding since, duetothehighurinehypo-osmoticloss,severe mmol/kg H mEq/L with a concomitant urine osmolality less than 200 chart willdocumentaplasmasodiumhigherthan145 NDIsincedataobtainedfromthehospital hereditary A dehydrationtestisoftennotindicatedinpatientswith measurements infamilialNDI Water deprivationtestsandcopeptin augmentations ofplasmasodium( and salineretainedwithdangerous,potentiallylethal, forbidden inpatientswithNDIsincewaterisexcreted intravenous administration of solutions is strictly proof-of-concept clinicalstudieshavebeendone( V2R signallinghasbeentestedexperimentallybutno better toleratedandefficacious.Bypassingthevasopressin symptoms) orwithdomperidone,whichseemstobe metoclopramide (whichcouldinduceextrapyramidal improve withtheabsorptionofanH2blockerand gastroesophageal reflux.Theseyoungpatientsoften vomit becauseofanexacerbationphysiologic have beenreported( of commencingindomethacinandhydrochlorothiazide with rapidloweringofplasmasodiumlevelsasaresult when firstinitiatedandhyponatraemicseizuresassociated complicated. The effect of these drugs can be quite marked in the first years of life when management is the most anhydrase bythiazidemightbeinvolved( volume contraction. A possibleinhibition of carbonic a mercurial diureticlikelyinducingthesameextracellular with of thethiazidederivatives since itwasalsoobserved intake. Thethiazideeffectisnotduetoauniqueproperty osmolality afterthiazideadministrationandlowsodium Review Inhibitors ofprostaglandinsynthesisareprescribed 2 O. Further, adehydrationtestisdangerous ≤ 55 200 mosmol/kg).Ifthediagnosisis 53 ). ). Manyaffectedinfantsfrequently D GBichet 54 ). 52 ). 16 ). The

Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest based ontheabsenturineosmolalityresponsetodDAVP. toconfirmthediagnosis measurements arenotnecessary normal vasopressinresponsetodehydration.These NDI, thatishigherthan21.4pg/mL( and theplasmasodiumconcentrationareessential. tests,urineandplasmaosmolalities, weight, laboratory signs (temperature, pulse, and ), body more than5%oftheirbodyweight.Monitoringvital Thepatientshouldnotbeallowedtolose supervision. should beperformedinthehospitalunderclosemedical References Foundation Kidney the from grants by of Canada. and MA9315) and (MT8126 Research Health of Institutes Canadian the by funded was research This insipidus Familial nephrogenicdiabetes 8 9 7 6 5 4 3 2 1 Spiegel AM &Weinstein LS. InheriteddiseasesinvolvingG Feldman BJ, Rosenthal SM,Vargas GA, Fenwick RG,Huang EA, Bankir L, Fernandes S,Bardoux P, Bouby N&Bichet DG. Yang B &Bankir L.Ureaandurineconcentratingability:new Klussmann E, Maric K&Rosenthal W. Themechanismsofaquaporin Noda Y, Sohara E,Ohta E&Sasaki S.Aquaporinsinkidney Kozono D, Yasui M, King LS&Agre P. Aquaporinwaterchannels: Bichet DG. Regulationofthirstandvasopressinrelease. Nielsen S, Marples D,Frokiaer J,Knepper M&Agre P. Theaquaporin 1920–1928. et al. Matsuda-Abedini M, Lustig RH,Mathias RS, Portale AA,Miller WL med.55.091902.103843) Medicine proteins andGprotein-coupledreceptors. healthy humans. Vasopressin-V2 receptorstimulation reducessodiumexcretionin ajprenal.00367.2004) Renal Physiology insights fromstudiesinmice. BFb0119577) and Pharmacology control intherenalcollectingduct. (https://doi.org/10.1038/nrneph.2009.231) pathophysiology. org/10.1172/JCI15851) ofClinicalInvestigation Journal atomic structuremoleculardynamicsmeetclinicalmedicine. annurev-physiol-020518-114556) Review ofPhysiology 1718–1723. pathophysiology ofaquaporin-2. family ofwaterchannelsinkidney:anupdateonphysiologyand Plasma copeptinmeasurementsarehighinfamilial Water deprivationtestsforolderinfantsandchildren Nephrogenicsyndromeofinappropriate antidiuresis. 2004 (https://doi.org/10.1681/ASN.2004121079) (https://doi.org/10.1038/ki.1996.254) 55 2005 2000 Journal oftheAmericanSocietyNephrology Journal 27–39. Nature Reviews:Nephrology 2019 288 141 81 F881–F896. (https://doi.org/10.1146/annurev. Downloaded fromBioscientifica.com at09/27/202102:36:38PM 33–95. 359–373. 2002 American Journal ofPhysiology: American Journal Kidney International (https://doi.org/10.1007/ 109 Reviews ofPhysiology, Biochemistry (https://doi.org/10.1146/ (https://doi.org/10.1152/ 1395–1399. 183 2010 Annual Reviewof :2 56 6 168–178. ) reflectinga (https://doi. 1996 Annual 49

2005

R38 16 via freeaccess

European Journal of Endocrinology

24 23 Lacombe UL. 22 21 20 19 18 17 16 15 14 13 12 11 10 Review Christensen JH &Rittig S.Familialneurohypophyseal diabetes Reeves WB &Andreoli TE.Nephrogenicdiabetesinsipidus.In McIlraith CH. Notesonsomecasesofdiabetesinsipiduswithmarked Niaudet P, Dechaux M,Trivin C, Loirat C&Broyer M.Nephrogenic Hoekstra JA, vanLieburg AF, Monnens LA,Hulstijn-Dirkmaat GM Fujimoto M, Okada S,Kawashima Y, Nishimura R,Miyahara N, Crawford JD &Bode HH.Disordersoftheposteriorpituitary Bockenhauer D &Bichet DG.Pathophysiology, diagnosis Biebermann H, Kleinau G,Schnabel D,Bockenhauer D,Wilson LC, Miyado M, Fukami M,Takada S, Terao M, Nakabayashi K,Hata K, Timper K, Fenske W, Kuhn F, Frech N,Arici B, Rutishauser J,Kopp P, Bockenhauer D, Penney MD,Hampton D,van’t Hoff W, Erdelyi LS, Mann WA, Morris-Rosendahl DJ,Gross U,Nagel M, Carpentier E, Greenbaum LA,Rochdi D,Abrol R,Goddard3rdWA, (https://doi.org/10.1016/j.semnephrol.2006.03.003) insipidus –anupdate. Rignoux, 1841. Scriver, ALBeaudet,WSSly&DValle. NewYork: McGraw-Hill,1995. Metabolic BasisofInheritedDisease doi.org/10.1016/S0140-6736(01)87712-6) tendencies. family andhereditary in Nephrology from the NeckerHospital diabetes insipidus:clinicalandpathophysiologicalaspects. 8628(19960102)61:1<81::AID-AJMG17>3.0.CO;2-S) Medical Genetics with congenitalnephrogenicdiabetesinsipidus. & Knoers VV. Cognitiveandpsychosocialfunctioningofpatients inJapan. survey ofnephrogenicdiabetesinsipidusbasedonanationwide overview Kawaba Y, Hanaki K,Nanba E,Kondo Y, Igarashi T Saunders, 1975. Adolescence in children.In nrneph.2015.89) Reviews: Nephrology and managementofnephrogenicdiabetesinsipidus. doi.org/10.1210/jc.2018-01250) Clinical EndocrinologyandMetabolism multisystem disordercausedbytheGalphasmutationp. Tully I, Kiff S,Scheerer P, Reyes M,Paisdzior S org/10.1681/ASN.2018121268) the AmericanSocietyofNephrology in nephrogenicsyndromeofinappropriateantidiuresis. gain-of-function variantsofGsalpha-codingGNASgeneidentified Matsubara Y, Tanaka Y, Sasaki G,Nagasaki K 4507) Metabolism prospective multicenterstudy. in thedifferentialdiagnosisofpolyuria-polydipsiasyndrome:a Allolio B, Stettler C,Muller B org/10.1053/j.ajkd.2011.09.026) ofKidneyDiseases American Journal and thenephrogenicsyndromeofinappropriateantidiuresis. Gullett A, Sailesh S&Bichet DG.Afamilywithhyponatremia org/10.1038/ki.2015.181) diuresis. receptor gene,AVPR2, causesnephrogenicsyndromeofinappropriate Varnai P, Balla A&Hunyady L. MutationintheV2vasopressin 23 infant withNSIAD. activating F229VsubstitutionintheV2vasopressinreceptoran Bichet DG &Bouvier M.Identificationandcharacterizationofan org/10.1056/NEJMoa042743) ofMedicine New EnglandJournal 1635–1640. Kidney International 2015 , 2nded.,pp126–158.EdLIGardner. Philadelphia:W.B. De laPolydipsie Endocrine andGeneticDiseasesofChildhood (https://doi.org/10.1681/ASN.2012010077) 1996 Yonago ActaMedica 100 2015 Journal oftheAmericanSocietyNephrology Journal 2268–2274. 61 Seminars inNephrology 81–88. 11 576–588. 2015 , p87.Paris:ImprimerieetFonderie de et al. Journal ofClinicalEndocrinologyand Journal 2005 (https://doi.org/10.1002/(SICI)1096- 2019 , 7thed.,pp3045–3071.EdsCR (https://doi.org/10.1210/jc.2014- 88 Diagnosticaccuracyofcopeptin 2012 Lancet 2014 1984 2019 1070–1078. 352 D GBichet (https://doi.org/10.1038/ 30 1892 59 1884–1890. 877–889. 57 13 104 566–568. 85–91. 2006 et al. 247–260. et al. 140 1079–1089. American Journal of American Journal Germline-derived (https://doi. 767–768. Anew 26 et al. (https://doi. Nature (https://doi. 209–223. (https://doi. Clinical Journal of Journal Journal of Journal Advances (https:// (https:// The 2012

insipidus Familial nephrogenicdiabetes 27 30 37 36 35 34 33 32 31 29 28 26 25 38 Bode HH &Crawford JD.Nephrogenicdiabetesinsipidusin Makita N, Sato T, Yajima-Shoji Y, Sato J,Manaka K,Eda- Bockenhauer D, Carpentier E,Rochdi D,Van’t Hoff W, Breton B, Ulloa-Aguirre A, Janovick JA,Brothers SP&Conn PM.Pharmacologic Bernier V, Morello JP, Zarruk A,Debrand N,Salahpour A, Morello JP, Salahpour A,Laperrière A,Bernier V, Arthus MF, Vaithinathan R, Berson EL&Dryja TP. Furtherscreeningofthe polyuricdisorders:newconceptsand Bichet DG. Hereditary Bichet DG, Arthus MF, Lonergan M,Hendy GN,Paradis AJ, Arthus MF, Lonergan M,Crumley MJ,Naumova AK,Morin D,De Bichet DG, Razi M,Arthus MF, Lonergan M,Tittley P, Smiley RK, Shalev H, Romanovsky I,Knoers NV, Lupa S&Landau D.Bladder Ulinski T, Grapin C,Forin V, Vargas-Poussou R, Deschenes G& Yamashita S, Hata A,Usui T, Oda H,Hijikata A, Shirai T, Kaneko N & 1262–1268. a non-peptideV2Ragonist. nephrogenic diabetesinsipidushighlights asustainablesignalingby of theV2vasopressinreceptor(V2R)mutationscausingpartial Hashimoto M, Ootaki M, Matsumoto N, Nangaku M &Iiri T. Analysis org/10.1159/000245059) diabetes insipidus. mutation: molecularbasisofpartialandcompletenephrogenic Bernier V, Bouvier M & Bichet DG. Vasopressin Type 2 receptor V88M org/10.1111/j.1600-0854.2004.00232.x) treatment ofhumandisease. rescue ofconformationally-defectiveproteins:implicationsforthe ASN.2005080854) Society ofNephrology X-linked nephrogenicdiabetesinsipidus. et al. Lonergan M, Arthus MF, Laperriere A,Brouard R,Bouvier M JCI8688) Clinical Investigation function ofmisfoldedV2vasopressinreceptormutants. Pharmacological chaperonesrescuecell-surfaceexpressionand Lonergan M, Petäjä-Repo U,Angers S,Morin D,Bichet DG geno.1994.1301) pigmentosa. rhodopsin geneinpatientswithautosomaldominantretinitis (https://doi.org/10.1016/j.semnephrol.2006.02.004) differential diagnosis. NEJM196904032801404) of Medicine North America:theHopewellhypothesis. and theHopewellhypothesis. X-linked nephrogenicdiabetesinsipidusmutationsinNorthAmerica Rosenthal W &Didwania A. Fujiwara TM, Morgan K,Gregory MC, Society ofNephrology X-linked nephrogenicdiabetesinsipidus. of 33novel Marco LA, Kaplan BS,Robertson GL,Sasaki S,Morgan K ki.1989.272) Kidney International Evidence forapre-cyclicAMPV2receptordefectivemechanism. in patientswithcongenitalnephrogenicdiabetesinsipidus. Rock G &Hirsch DJ.EpinephrineanddDAVP administration (https://doi.org/10.1093/ndt/gfg574) insipidus. function impairmentinaquaporin-2defectivenephrogenicdiabetes 2928–2929. diabetes insipidus. receptor genemutationresponsibleforX-linkednephrogenic Bensman A. SeverebladderdysfunctioninafamilywithADH Hata D. NovelAVPR2 mutationcausingpartialnephrogenic diabetes 22460–22471. Pharmacologicchaperonesasapotentialtreatmentfor Nephrology, Dialysis,Transplantation 1969 AVPR2 (https://doi.org/10.1172/JCI116698) (https://doi.org/10.1093/ndt/gfh486) Genomics (https://doi.org/10.1074/jbc.M116.733220) 280 mutationsandanalysisof117familieswith Physiology Nephrology, Dialysis,Transplantation 1989 2006 2000 2000 750–754. 1994 Seminars inNephrology 36 17 11 105 Downloaded fromBioscientifica.com at09/27/202102:36:38PM Journal ofBiologicalChemistry Journal 21 859–866. 232–243. 1044–1054. Traffic 887–895. Journal ofClinicalInvestigation Journal 461–463. (https://doi.org/10.1056/ 2004 https://eje.bioscientifica.com 2010 (https://doi.org/10.1038/ (https://doi.org/10.1681/ (https://doi.org/10.1172/ (https://doi.org/10.1006/ 5 Journal oftheAmerican Journal Journal oftheAmerican Journal New England Journal New EnglandJournal 821–837. 183 114 2006 2004 :2 1–10. 26 19 224–233. (https://doi. (https://doi. 608–613. 2004 Journal of Journal et al. 2016 et al. 1993 19 Report R39 291

92 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

41 48 47 46 45 44 43 42 40 39 Review Chiu EKL, Hui WWI&Chiu RWK. cfDNAscreeninganddiagnosis Bianchi DW &Chiu RWK. Sequencingofcirculating cell-free Jeck N, Schlingmann KP, Reinalter SC,Komhoff M,Peters M, Gahl WA, Thoene JG&Schneider JA.Cystinosis. Marr N, Bichet DG,Lonergan M,Arthus MF, Jeck N, Calvanese L, D’Auria G,Vangone A, Falcigno L &Oliva R.Structural Frick A, Eriksson UK,deMattia F, Oberg F, Hedfalk K,Neutze R, Bichet DG, ElTarazi A, Matar J,Lussier Y, Arthus MF, Lonergan M, Schernthaner-Reiter MH, Adams D,Trivellin G, Ramnitz MS, Peces R, Mena R,Peces C,Santos-Simarro F, Fernandez L,Afonso S, 2018 of monogenicdisorders–whereareweheading? 464–473. DNA duringpregnancy. R782–R795. Physiology: Regulatory, IntegrativeandComparativePhysiology lessons learnedfrominheritedhumandisorders. Waldegger S &Seyberth HW. Salthandlinginthedistalnephron: NEJMra020552) ofMedicine Journal Genetics explains dominantnephrogenicdiabetesinsipidus. Aquaporin-2 andtheirmisroutingtolateendosomes/lysosomes Heteroligomerization ofanAquaporin-2mutantwithwild-type Seyberth HW, Rosenthal W, vanOs CH,Oksche A&Deen PM. (https://doi.org/10.3390/ijms19061577) diseases. basis formutationsofhumanaquaporinsassociatedtogenetic org/10.1073/pnas.1321406111) insipidus andtrafficking. human aquaporin2anditsimplicationsfornephrogenicdiabetes de Grip WJ,Deen PM&Tornroth-Horsefield S. X-raystructureof mgg3.568) and GenomicMedicine deletion oftheAQP2gene.Acasereport. diabetes insipidusinacompoundheterozygotewithnewlarge Lapunzina P, Selgas R&Nevado J.Severecongenitalnephrogenic (https://doi.org/10.1093/ckj/sfs029) update andepidemiology. responsible forautosomal-recessivenephrogenicdiabetesinsipidus- Bockenhauer D &Bissonnette P. Aquaporin-2:newmutations 2684-4) Pediatrics nephrogenic diabetesinsipidusintwobrothers. et al. Raygada M, Golas G,Faucz FR,Nilsson O,Nella AA,Dileepan K 0323) Metabolism insipidus inaJapanesefamily. AnovelAVPR2 splicesitemutationleadstopartialX-linked 38 2002 52–58. 2016 International Journal ofMolecularSciences Journal International (https://doi.org/10.1056/NEJMra1705345) 2016 (https://doi.org/10.1152/ajpregu.00600.2004) 11 175 (https://doi.org/10.1002/pd.5207) 779–789. 29 2002 727–733. 591–596. 2019 347 New England Journal ofMedicine New EnglandJournal PNAS Clinical KidneyJournal (https://doi.org/10.1093/hmg/11.7.779) 7 111–121. e00568. (https://doi.org/10.1007/s00431-015- (https://doi.org/10.1515/jpem-2015- Journal ofPediatricEndocrinologyand Journal 2014 111 D GBichet (https://doi.org/10.1002/ (https://doi.org/10.1056/ 6305–6310. Molecular Genetics European Journal of European Journal 2012 2018 American Journal of American Journal New England Prenatal Diagnosis Human Molecular (https://doi. 5 19 2018 195–202. E1577. 2005 379 288

Accepted 6May2020 Revised versionreceived20April2020 Received 11February2020

insipidus Familial nephrogenicdiabetes 56 55 54 52 51 50 49 60 59 58 57 53 Fenske W, Refardt J,Chifu I,Schnyder I,Winzeler B, Drummond J, Bichet DG. Evaluationofpatientwithpolyuria.In Bockenhauer D &Bichet DG.Nephrogenicdiabetesinsipidus. Boussemart T, Nsota J,Martin-Coignard D&Champion G. Sinke AP, Kortenoeven ML,deGroot T, Baumgarten R, Devuyst O, Earley LE &Orloff J.Themechanismofantidiuresisassociated Crawford JD &Kennedy GC.Chlorothiazidindiabetesinsipidus. Bockenhauer D, van’t Hoff W, Dattani M,Lehnhardt A,Subtirelu M, Deen PMT, Verdijk MAJ, Knoers NVAM, Wieringa B, Monnens LAH, Laghmani K, Beck BB,Yang SS, Seaayfan E,Wenzel A, Kleta R &Bockenhauer D.Salt-losingtubulopathiesinchildren: Nielsen S, Pallone T, Smith BL,Christensen EI,Agre P& UpToDate, 2020. MOP.0000000000000473) Opinion inPediatrics 2009 Nephrogenic diabetesinsipidus:treatwithcaution. ajprenal.00617.2013) Renal Physiology the sodium-chloridecotransporter. lithium-induced nephrogenicdiabetesinsipidusindependentlyof Wetzels JF, Loffing J&Deen PM.Hydrochlorothiazideattenuates JCI104657) Investigation with vasopressin-resistantdiabetesinsipidus. with theadministrationofhydrochlorothiazidetopatients Nature Physiology insipidus asacomplicationofinheritedrenaldiseases. nephrogenicdiabetes Hildebrandt F &Bichet DG.Secondary science.8140421) of urine. channel aquaporin-2forvasopressin-dependentconcentration van Os CH&Oost BA.Requirementofhumanrenalwater 1853–1863. MAGED2 mutations. Polyhydramnios, transientantenatalBartter’s syndrome,and Reusch B, Vitzthum H, Priem D,Demaretz S,Bergmann K ASN.2017060600) of Nephrology what’s new, what’s controversial? org/10.1152/ajprenal.1995.268.6.F1023) ofPhysiology American Journal descending thinlimbsandinvasarectaratkidney. Maunsbach AB. Aquaporin-1waterchannelsinshortandlongloop NEJMoa1803760) ofMedicine Journal based approachinthediagnosisofdiabetesinsipidus. Ribeiro-Oliveira JrA,Drescher T, Bilz S,Vogt DR 24 1959 1761–1763. Science 2010 1962 (https://doi.org/10.1056/NEJMoa1507629) 183 2018 2014 1994 116 891–892. 41 2018 29 2017 p23–p29. (https://doi.org/10.1007/s00467-009-1187-9) 1988–1997. New England Journal ofMedicine New EnglandJournal 727–739. 306 264 379 29 F525–F533. 92–95. Downloaded fromBioscientifica.com at09/27/202102:36:38PM (https://doi.org/10.1038/183891a0) 428–439. 199–205. 1995 (https://doi.org/10.1159/000320117) (https://doi.org/10.1681/ (https://doi.org/10.1172/ (https://doi.org/10.1126/ Journal oftheAmericanSociety Journal 268 American Journal ofPhysiology: American Journal (https://doi.org/10.1152/ (https://doi.org/10.1056/ (https://doi.org/10.1097/ F1023–F1037. 183 Journal ofClinical Journal :2 et al. Pediatric Nephrology Uptodate 2016 Acopeptin- New England (https://doi. Nephron. et al. 374 . R40 Current

via freeaccess