review article mechanisms of disease mutations affecting

MECHANISMS OF DISEASE

Volume 340 Number 15

·

1177

Review Article

Mechanisms of Disease

F

RANKLIN

H. E

PSTEIN

, M.D.,

Editor

G

ENETIC

D

ISORDERS

OF

R

ENAL

E

LECTROLYTE

T

RANSPORT

S

TEVEN

J. S

CHEINMAN

, M.D., L

ISA

M. G

UAY

-W

OODFORD

, M.D., R

AJESH

V. T

HAKKER

, M.D.,

AND

D

AVID

G. W

ARNOCK

, M.D.

From the Department of Medicine, State University of New York HealthScience Center, Syracuse (S.J.S.); the Departments of Medicine (L.M.G.-W.,D.G.W.), Pediatrics (L.M.G.-W.), and Physiology (D.G.W.), University ofAlabama at Birmingham, Birmingham; and the Medical Research CouncilMolecular Endocrinology Group, Hammersmith Hospital, London (R.V.T.).Address reprint requests to Dr. Scheinman at the Department of Medicine,SUNY Health Science Center, 750 East Adams St., Syracuse, NY 13210,or at [email protected].

©1999, Massachusetts Medical Society.

N the 1950s and 1960s, several inherited disor-ders of fluid and electrolyte metabolism were de-scribed in which the principal disturbance ap-

peared to be a specific functional defect in the renaltubule. For most of these diseases, plausible physio-logic explanations were presented, some more con-vincing than others. In the past five years, geneticand molecular approaches have elucidated the un-derlying molecular defects in several of these disor-ders. In some instances, predictions based on theinitial physiologic studies have been confirmed; inothers, the molecular answer has come as a surprise,raising further questions about the physiology of ep-ithelial function. In several cases, the discovery ofthe molecular defect in a rare mendelian disorderhas provided important insights into complex traits,such as hypertension and hypercalciuria.

A variety of inherited disorders alter specific renalepithelial transport functions (Table 1). This reviewaddresses those in which the transport of electrolytesor minerals by the renal tubular epithelium is de-ranged and the defect has been attributed to a spe-cific transport protein. This review does not includedisorders in which the principal disturbance involvesthe transport of bicarbonate or protons (e.g., renaltubular acidosis). The disorders reviewed and thenephron segments affected are shown in Figure 1.

I

MUTATIONS AFFECTING THE EPITHELIAL

SODIUM CHANNEL

Liddle’s Syndrome

In 1963 Liddle and colleagues described a familialsyndrome of severe hypertension, hypokalemia, andmetabolic alkalosis that mimicked hyperaldosteron-ism.

2

Clinical studies revealed that affected patientshad exceptionally low rates of aldosterone secretion,hyporeninemia, no response to spironolactone, and aresponse to triamterene and salt restriction. Liddleet al. stated, “The disorder apparently stems from anunusual tendency of the kidneys to conserve sodiumand excrete potassium even in the virtual absence ofmineralocorticoids.”

2

This mechanism was confirmedby the fact that the disorder resolved after renaltransplantation in the proband, in whom renal fail-ure had developed 25 years after the original study.

3

Studies of the original pedigree revealed an autoso-mal dominant mode of inheritance

4

; ultimately, mu-tations affecting the cytosolic tail of the

b

subunit ofthe epithelial sodium channel were found in this andfour other, smaller kindreds.

5,6

These mutations cause constitutive activation of theepithelial sodium channel in the luminal membraneof the collecting tubule (Fig. 2) and provide a path-ophysiologic basis for this rare form of low-reninhypertension. Unregulated reabsorption of sodiumacross the collecting tubule results in volume expan-sion, inhibition of renin and aldosterone secretion,and hypertension.

4,5

Similar activating mutations havebeen described that affect the

g

subunit of the epi-thelial sodium channel and, more recently, a similarproline-rich region of either the

b

or the

g

subunit,which also result in constitutive activation of the so-dium channel, with the same pathophysiologic ef-fects.

7

This proline-rich region interacts with cyto-skeletal proteins that may regulate the expression ofthe channel complex at the luminal membrane.

8

Although the precise mechanism of the constitu-tive activation in Liddle’s syndrome is still debated(increased dwelling time in the plasma membrane

9

vs. direct kinetic activation

10

), it is certain that theinteraction of the epithelial sodium channel with cy-toskeletal proteins regulates its activity. The lack ofdown-regulation of the epithelial sodium channel inthe face of persistent volume expansion underlies thepathophysiology of this syndrome. A similar lack ofdown-regulation of the activity of the epithelial so-dium channels may underlie more common formsof low-renin hypertension. Although truncating orother activating mutations of the genes for the so-dium-channel subunits are uncommon in patients

Copyright © 1999 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIVERSITATSBIBLIOTHEK on April 18, 2007 .

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Apr i l 15, 1999

The New England Journal of Medicine

*Entries in italics indicate that the mode of inheritance or associations have not been firmly established.

†OMIM denotes Online Mendelian Inheritance in Man

1

(also at http://www.ncbi.nlm.nih.gov/Omim/).

T

ABLE

1.

R

ENAL

T

UBULAR

D

ISORDERS

I

NHERITED

AS

M

ENDELIAN

T

RAITS

.*

I

NHERITED

D

ISORDER

M

ODE

OF

T

RANSMISSION

D

EFECTIVE

P

ROTEIN

OMIMN

O

.†

Renal glucosuria

Autosomal recessive, auto-somal dominant, or both

Sodium–glucose transporter 2

233100

Glucose–galactose malabsorption syndrome

Autosomal recessive Sodium–glucose transporter 1 182380

Dicarboxylic aminoaciduria Autosomal recessive

Sodium- and potassium-dependent glutamate transporter

222730

Dibasic aminoaciduria (lysinuric pro-tein intolerance)

Autosomal recessive Basolateral dibasic amino acid transporter 222700

Neutral aminoaciduria Unknown

Neutral amino acid transporter

Hartnup’s disorder 234500Blue diaper syndrome 211000Homocystinuria 236200Cystathioninuria 219500Iminoglycinuria 242600Glycinuria 138500Tyrosinemia 276700

Hereditary hypophosphatemic rickets with hypercalciuria

Autosomal recessive

Sodium–phosphate transporter

241530

X-linked hypophosphatemic rickets X-linked dominant PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) protein

307800

Oculocerebrorenal syndrome of Lowe X-linked Inositol polyphosphate 5-phosphatase 309000

Inherited Fanconi’s syndrome (he-reditary fructose intolerance)

Autosomal recessive Aldolase B 229600

Carbonic anhydrase II deficiency Autosomal recessive Carbonic anhydrase type II 259730

Distal renal tubular acidosis Autosomal recessiveAutosomal dominant

B1 subunit of proton ATPaseBasolateral anion exchanger

602722179800

Bartter-like syndromesAntenatal Bartter’s syndrome Autosomal recessive Bumetanide-sensitive sodium–potassium–2-chloride

transporter (NKCC2), ATP-regulated potassium channel (ROMK), kidney-specific chloride channel (ClC-Kb)

601678

Classic Bartter’s syndrome Autosomal recessive Kidney-specific chloride channel (ClC-Kb) 602023Gitelman’s syndrome Autosomal recessive Thiazide-sensitive sodium–chloride transporter (NCCT) 263800

PseudohypoparathyroidismType Ia Autosomal dominant Guanine nucleotide–binding protein (G

s

) 103580Type Ib Unknown Unknown 603233

Familial benign hypocalciuric hyper-calcemia

Autosomal dominant Calcium-sensing receptor (inactivation) 145980

Neonatal severe hyperparathyroidism Autosomal recessive Calcium-sensing receptor (inactivation) 239200

Familial hypercalciuric hypocalcemia Autosomal dominant Calcium-sensing receptor (activation) 601198

Low-renin hypertensionGlucocorticoid-remediable aldoste-

ronismAutosomal dominant 11

b

-Hydroxylase and aldosterone synthase (chimeric gene) 103900

Liddle’s syndrome Autosomal dominant

b

and

g

subunits of the epithelial sodium channel 177200Syndrome of apparent mineralocor-

ticoid excessAutosomal recessive 11

b

-Hydroxysteroid dehydrogenase type II 218030

PseudohypoaldosteronismType I Autosomal recessive

Autosomal dominant

a

,

b

,

g

subunits of the epithelial sodium channelMineralocorticoid (type I) receptor

264350177735

Type II (Gordon’s syndrome) Autosomal dominant Unknown 145260

Nephrogenic diabetes insipidusX-linked X-linked Vasopressin V2 receptor 304800Autosomal Autosomal recessive and

autosomal dominantAquaporin-2 water channel 222000

UrolithiasisCystinuria type I Autosomal recessive Apical cystine–dibasic amino acid transporter 220100Cystinuria types II and III Autosomal recessive Unknown 600918Dent’s disease X-linked Renal chloride channel (ClC-5) 300008X-linked recessive nephrolithiasis X-linked Renal chloride channel (ClC-5) 300008X-linked recessive hypophos-

phatemic ricketsX-linked Renal chloride channel (ClC-5) 300008

Low-molecular-weight proteinuriawith nephrocalcinosis

X-linked Renal chloride channel (ClC-5) 300008

Hereditary renal hypouricemia Autosomal recessive

Urate transporter

220150Xanthinuria Autosomal recessive Xanthine oxidase 278300




·

1179

with hypertension, there may be polymorphisms inthe channel proteins that have more subtle, yet po-tentially important, effects on the regulation of epi-thelial sodium-channel activity.

11,12

Pseudohypoaldosteronism Type I

There are also clinical syndromes that reflect theloss of sodium-channel activity. One is a familial formof mineralocorticoid resistance known as pseudohy-poaldosteronism type I that is associated with renalsalt wasting; high concentrations of sodium in sweat,stool, and saliva; hyperkalemia and increased plasmarenin activity; and high serum aldosterone concen-trations.

13

This autosomal recessive disorder involvesmultiple organ systems and is especially marked in theneonatal period, with vomiting, hyponatremia, failureto thrive, and occasionally the respiratory distresssyndrome. Respiratory tract infections are commonin affected children and may be mistaken for cysticfibrosis.

14

With aggressive salt replacement and con-trol of hyperkalemia, these children can survive, andthe disorder appears to become less severe with age.

The genes encoding the three subunits of the ep-ithelial sodium channel were obvious candidates forinvolvement in this disorder, and indeed, mutationsthat cause loss of function of the epithelial sodiumchannel have been described in each of the subunitgenes.

15,16

In addition, deletion of the

a

subunit inmice causes death from respiratory distress in theneonatal period,

17

presumably from the failure toclear alveolar fluid at the time of birth. If these miceare “rescued” from the respiratory failure by the en-gineered expression of the gene for the

a

subunit ofthe epithelial sodium channel in the lung, the micesurvive and have salt wasting and hyperkalemia.

18

There was initially some confusion in the descrip-tions of pseudohypoaldosteronism because of uncer-tainty about its inheritance and reports that there weredefects in the mineralocorticoid receptor in somekindreds. This issue has been clarified with the de-scription of four mutations affecting the epithelial so-dium channel in the recessive form of pseudohypoal-dosteronism type I and of four different mutationsaffecting the mineralocorticoid receptor in the auto-somal dominant form.

19

These patients present withsalt wasting and hyperkalemia but do not have pulmo-nary or other organ-system involvement. This resultwas anticipated by the finding that carbenoxolone,which inhibits 11

b

-hydroxysteroid dehydrogenase typeII, the enzyme that converts cortisol to cortisone,can partially correct the apparent mineralocorticoidresistance in these patients.

14

By slowing the conver-sion of cortisol to cortisone, carbenoxolone raisesthe intracellular cortisol concentration sufficiently tomaintain activation of the wild-type receptor, thusovercoming the functional defect in the mutant recep-tor. This mechanism is consistent with the presence ofhaploinsufficiency of the wild-type mineralocorticoid

Figure 1.

Nephron Segments Affected by Genetic Disorders forWhich the Gene Has Been Cloned.Proximal tubular function is altered by mutations affecting thePHEX (phosphate-regulating gene with homologies to en-dopeptidases on the X chromosome) protein in X-linked hypo-phosphatemic rickets, in which reabsorption of phosphate andhydroxylation of vitamin D are abnormal, and by mutations af-fecting the renal ClC-5 chloride channel in Dent’s disease. ClC-5is also expressed in the thick ascending limb of Henle’s loop. InBartter’s syndrome there are mutations in the genes encodingthe membrane transport proteins: sodium–potassium–2-chlo-ride transporter (NKCC2), the ATP-regulated potassium channel,and kidney-specific chloride channel ClC-Kb. These genes areexpressed in the cells of the thick ascending limb. Mutations inthe gene encoding the sodium–chloride transporter in the dis-tal convoluted tubule cause Gitelman’s syndrome. Mutations inthe gene encoding the calcium-sensing receptor alter the func-tion of the ascending limb of Henle’s loop and the collectingduct and cause familial hypocalciuric hypercalcemia. Activat-ing mutations in the gene encoding the epithelial sodiumchannel in Liddle’s syndrome stimulate the reabsorption of so-dium chloride in the collecting duct, and inactivating muta-tions in the genes encoding the epithelial sodium channel orthe mineralocorticoid receptor give rise to pseudohypoaldos-teronism type I.

Gitelman’ssyndrome

Bartter’ssyndrome

X-linkedhypophosphatemic

rickets

Familialhypocalciuric

hypercalcemia

Liddle’s syndromePseudohypoaldosteronism

type I

Dent’sdisease


1180

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Apr i l 15, 1999


receptor in this autosomal dominant form of pseudo-hypoaldosteronism, whereas the multiorgan defects inthe recessive form are explained by loss-of-functionmutations in the genes for subunits of the epithelialsodium channel.

MUTATIONS AFFECTING DIURETIC-

SENSITIVE SODIUM-TRANSPORT

PROTEINS

Bartter’s Syndrome

In 1962 Bartter and colleagues described hypoka-lemic, hypochloremic metabolic alkalosis in two chil-dren and a man.

20

Other characteristics of the disorderare increased urinary excretion of potassium andprostaglandins, normal or low blood pressure despiteincreased plasma renin activity and high serum al-dosterone concentrations, a relative vascular resist-ance to the pressor effects of exogenous angiotensinII, and hyperplasia of the juxtaglomerular appara-tus.

20,21

In most patients, the disease is diagnosed ininfancy, childhood, or early adolescence. There is nopredilection with respect to race, ethnic group, or sex.Although many cases appear to be sporadic, Bartter’ssyndrome does occur in families, with an autosomalrecessive mode of inheritance.

21

Bartter’s syndrome is not a single disease but a setof closely related renal tubular disorders. At leastthree phenotypic subgroups have been identified: anantenatal hypercalciuric variant, also termed hyper-prostaglandin E syndrome, which is characterized byhydramnios, prematurity, and dehydration at birth;classic Bartter’s syndrome, which presents in chil-dren, often as failure to thrive; and a hypocalciuric–hypomagnesemic variant known as Gitelman’s syn-

Figure 2.

Aldosterone-Regulated Transport in the Cortical Col-lecting Tubule.Mineralocorticoids regulate electrolyte balance through theiraction in the principal cells of the cortical collecting tubule. Thetype I mineralocorticoid receptor binds both aldosterone andcortisol, but not cortisone. The specificity of the receptor foraldosterone is mediated by the type II kidney isoform of 11

b

-hydroxysteroid dehydrogenase (not shown), which convertscortisol to cortisone. Under normal conditions, the epithelialsodium channel is the rate-limiting barrier for the entry of sodi-um from the lumen into the cell (Panel A). The resulting lumen-negative transepithelial voltage (indicated by the minus sign)drives potassium secretion from the principal cells and protonsecretion from the intercalated cells (not shown). In Liddle’ssyndrome, mutations in the gene encoding the epithelial sodiumchannel result in persistent unregulated reabsorption of so-dium and increased secretion of potassium (not shown). In au-tosomal recessive pseudohypoaldosteronism type I (Panel B),loss-of-function mutations in this gene inactivate the channel.In autosomal dominant pseudohypoaldosteronism type I (Pan-el C), mutations in the gene encoding the mineralocorticoid re-ceptor disrupt mineralocorticoid regulation of the activity ofthe epithelial sodium channel. Either mechanism reduces theactivity of the epithelial sodium channel, thus causing saltwasting and decreasing the secretion of potassium and protons.

Lumen

A

Blood

Na+

Epithelialsodiumchannel

–

K+

Na+

Mineralocorticoidreceptor

Lumen

B

Blood

–

Na+

Lumen

C

Blood

K+

K+

–

K+

Na+


Na+



K+

Na+

K+

Aldosterone


Aldosterone

Aldosterone

Normal Kidney

Autosomal Recessive PseudohypoaldosteronismType I

Autosomal Dominant PseudohypoaldosteronismType I




·

1181

drome, which often presents in adults.

21

This heter-ogeneity and the diverse array of physiologic derange-ments long confounded efforts to understand thefundamental defects in these syndromes. Proposedprimary defects included juxtaglomerular hyperpla-sia; insensitivity to angiotensin II; overproduction ofprostaglandins, kallikrein, and kinins; a defect in po-tassium transport resulting in excessive urinary potas-sium excretion; and a defect in sodium chloride trans-port in the thick ascending limb of Henle’s loop orthe distal convoluted tubule.

21,22

Among the causesof hypokalemic metabolic alkalosis, the absence of hy-pertension rules out primary mineralocorticoid ex-cess, and the finding of high urinary chloride excre-tion rules out secondary hyperaldosteronism due toextrarenal fluid loss. These findings occur only in Bart-ter’s syndrome and with long-term diuretic therapy.

23

These and other clinical data suggested that Bart-ter’s syndrome results from defective transepithelialtransport of sodium chloride in the thick ascendinglimb of Henle’s loop. The genes encoding several pro-teins of the thick ascending limb have been cloned, in-cluding the genes encoding the bumetanide-sensitivesodium–potassium–2-chloride transporter (

NKCC2

),the apical ATP-regulated potassium channel (

ROMK

),and the kidney-specific basolateral chloride channel(

ClC-Kb

). Loss-of-function mutations in the genesfor each of these transport proteins have been doc-umented in some, but not all, patients with antena-tal Bartter’s syndrome or the more classic pheno-type.

24-28

As shown in Figure 3, sodium chloride transportin the thick ascending limb involves a complex inter-play of transporters and channels. Defects in any ofthese proteins could impair the net reabsorption ofsodium chloride in the thick ascending limb andthereby increase delivery of sodium chloride to moredistal nephron segments, with consequent salt wast-ing, volume contraction, and stimulation of the re-nin–angiotensin–aldosterone axis, leading to hypo-kalemic metabolic alkalosis. Hypokalemia, chronicvolume contraction, and high plasma concentrationsof angiotensin, kallikrein, kinins, and vasopressin allstimulate the production of prostaglandin E

2

.

21

Thus,stimulation of renal and systemic production of pros-taglandin E

2

, which is especially marked in antenatalBartter’s syndrome, is likely to be secondary to theunderlying defect in the transport of sodium chlo-ride in the thick ascending limb.

Impaired transport of sodium chloride in the thickascending limb is associated with a reduction in thelumen-positive electrical transport potential that nor-mally drives the paracellular reabsorption of calciumand magnesium (Fig. 3),

30

causing increased urinaryloss of these ions. Hypercalciuria is a common fea-ture of Bartter’s syndrome and often leads to neph-rocalcinosis in antenatal Bartter’s syndrome. Hypo-magnesemia, in contrast, is uncommon.

Gitelman’s Syndrome

Gitelman’s syndrome is a variant of Bartter’s syn-drome in which patients have hypomagnesemia andhypocalciuria.

31

Thiazide diuretics inhibit the sodi-um–chloride transporter NCCT (also known as thethiazide-sensitive cotransporter) in the distal convo-luted tubule (Fig. 4), and patients with Gitelman’ssyndrome have a subnormal natriuretic response tointravenous chlorothiazide but a prompt natriuresisafter the administration of furosemide.

32

Mutationsassociated with a putative loss of function of the so-dium–chloride transporter NCCT have been identi-fied in patients with Gitelman’s syndrome.

33-35

Loss of function of this sodium–chloride trans-porter causes defective reabsorption of sodium chlo-ride in the distal convoluted tubule, which normallyreabsorbs about 7 percent of the filtered load of so-dium chloride. This defect increases solute delivery tothe collecting tubule, with consequent mild volumecontraction and aldosterone-stimulated secretion ofpotassium and protons, resulting in mild hypokale-mic metabolic alkalosis. The volume contraction, thestimulation of vasopressin and the renin–angioten-sin–aldosterone axis, and the potassium depletionappear to be less marked than in Bartter’s syndromeand are not sufficient to increase the production ofrenal and systemic prostaglandin E

2

substantially. Uri-nary prostaglandin excretion remains normal in pa-tients with Gitelman’s syndrome.

21

Pharmacologic inhibition of the function of thesodium–chloride transporter by thiazides stimulatesthe reabsorption of calcium by the distal convolutedtubule, and the mutations that inactivate this trans-porter in Gitelman’s syndrome presumably cause hy-pocalciuria in the same manner (Fig. 4). Thiazideslimit the entry of sodium chloride across the luminalmembrane of the cells of the distal convoluted tu-bule, and intracellular chloride continues to exitthrough basolateral chloride channels. This hyper-polarizes the cell and stimulates the entry of calciumthrough apical, voltage-activated calcium channels.

36

The impairment of sodium entry also lowers the in-tracellular sodium concentration and facilitates theexchange of sodium for calcium across the basolat-eral membrane. Thus, thiazides cause changes in boththe luminal entry of calcium and the basolateral exitof calcium that increase the reabsorption of calciumin the distal convoluted tubule, with resultant hypo-calciuria.

Magnesium Excretion in Bartter’s and Gitelman’s Syndromes

Diuretics and mutations causing inactivation of thetransport proteins have similar effects on the excre-tion of sodium chloride and calcium, but not onmagnesium excretion. Loop diuretics increase urinarymagnesium excretion, whereas thiazides have littleeffect on it. Most patients with Gitelman’s syndrome


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Figure 3.

Transport Mechanisms in the Thick Ascending Limb of the Loop of Henle.Sodium chloride is reabsorbed in the thick ascending limb by the bumetanide-sensitive sodium–potassium–2-chloride transporter(NKCC2). This electroneutral transporter is driven by the low intracellular sodium and chloride concentrations generated by Na

+

/K

+

–ATPase and the kidney-specific basolateral chloride channel (CIC-Kb). The availability of luminal potassium is rate-limiting forNKCC2, and recycling of potassium through the ATP-regulated potassium channel (ROMK) ensures the efficient functioning ofNKCC2 and generates a lumen-positive transepithelial potential. Genetic studies have identified putative loss-of-function mutationsin the genes encoding NKCC2, ROMK, and CIC-Kb in subgroups of patients with Bartter’s syndrome. In contrast to the normal con-dition (Panel A), loss of function of NKCC2 (Panel B) impairs reabsorption of sodium and potassium. Inactivation of the luminalROMK (Panel C) limits the amount of potassium available for NKCC2. Inactivation of the basolateral CIC-Kb (Panel D) reduces trans-cellular reabsorption of chloride. Loss of function of any of these transporters will reduce the transepithelial potential and thus de-crease the driving force for the paracellular reabsorption of cations. In most patients with Bartter’s syndrome, urinary calcium ex-cretion is increased. Activation of the calcium-sensing receptor (CaR) inhibits activity of the ROMK potassium channel and therebyreduces the reabsorption of solutes in this nephron segment.

29

Lumen

K+

A

Blood

+ –

K+

Na+

2 Cl–

K+

Na+

CaR

Na+, Mg2+, Ca2+

NKCC2

ROMK

Lumen

B

Blood

K+

Na+

2 Cl–

K+

Na+

Lumen

C

Blood

K+

Na+

2 Cl–

K+

Na+

Lumen

D

Blood

K+

Na+

2 Cl–

K+

Na+

Cl–

K+

ROMK

Cl–

K+

ROMK

K+

ROMK

Cl–

ClC-Kb

Cl–

NKCC2

NKCC2 NKCC2

CaR

CaR CaR

ClC-Kb

ClC-KbClC-Kb

Normal Kidney Bartter’s Syndrome: NKCC2 Mutation

Na+/K+–ATPase

Na+/K+–ATPaseNa+/K+–ATPase

Na+/K+–ATPase

Bartter’s Syndrome: ROMK Mutation Bartter’s Syndrome: CIC-Kb Mutation

Na+, Mg2+, Ca2+

Na+, Mg2+, Ca2+ Na+, Mg2+, Ca2+




· 1183

have increased urinary magnesium excretion andmarked hypomagnesemia, but in patients with Bart-ter’s syndrome, hypomagnesemia is uncommon and,when present, mild. The physiologic basis for thesedifferences in magnesium excretion is not known.

In mammals about 60 percent of filtered magne-sium is normally reabsorbed in the thick ascendinglimb, and 5 to 10 percent is reabsorbed in the distalconvoluted tubule; there is very little reabsorptionof magnesium in the collecting duct.37 The mecha-nisms for the reabsorption of magnesium in the distalconvoluted tubule are similar to those for calciumreabsorption and include a luminal magnesium chan-nel and a basolateral sodium–magnesium exchang-er.37 In addition, there may be specific magnesiumtransporters that have not yet been identified.38 Vol-ume depletion, metabolic alkalosis, and vasopressinstimulate magnesium transport in the distal convo-luted tubule, and aldosterone can potentiate this ef-fect of vasopressin.37,39 These hormonal actions appearto be counterbalanced by the effects of potassiumdepletion, which inhibits the reabsorption of mag-nesium in the distal convoluted tubule.37,40

On the basis of these physiologic observations, wepropose that net magnesium excretion is determinedby the balance of hormonal effects and intracellularpotassium stores in the distal convoluted tubule.Thus, the marked salt wasting and aldosterone stim-ulation in patients with antenatal or classic Bartter’ssyndrome may stimulate the reabsorption of magne-sium in the distal convoluted tubule, substantiallymitigating the magnesium wasting caused by thetransport defect in the thick ascending limb. Sinceloop diuretics are short-acting, there may be lessstimulation of magnesium reabsorption in the distalconvoluted tubule in patients treated with thesedrugs than in patients who have loss-of-functionmutations in the genes for relevant transport pro-teins. In Gitelman’s syndrome the volume depletion,metabolic alkalosis, and stimulation of aldosteronesecretion are less severe than in antenatal or classicBartter’s syndrome. The effect of hypokalemia maypredominate in this disorder and thus may explainthe profound magnesium wasting that is a cardinalfeature of Gitelman’s syndrome.

MUTATIONS AFFECTING AN

EXTRACELLULAR CALCIUM-SENSING

RECEPTOR

In 1972 a syndrome of “familial benign hypercalce-mia” was described in 11 members of a large family.41

Hypocalciuria was also noted, and therefore thiscondition is also known as familial hypocalciuric hy-percalcemia. The patients had mild hypermagnesemiaas well; their serum parathyroid hormone concentra-tions were normal or mildly elevated. Calcium-infu-sion studies revealed a higher-than-usual set point forthe release of parathyroid hormone in these patients,

Figure 4. Transport Mechanisms in the Distal Convoluted Tubule.Under normal conditions, sodium chloride is reabsorbed by theapical thiazide-sensitive sodium–chloride transporter (NCCT)in the distal convoluted tubule (Panel A). This electroneutraltransporter is driven by the low intracellular sodium and chlo-ride concentrations generated by Na+/K+–ATPase and an as yetundefined basolateral chloride channel. In this nephron seg-ment, there is an apical calcium channel and a basolateral so-dium-coupled exchanger. Physiologic evidence indicates thatthe mechanisms for the transport of magnesium are similar tothose for calcium. In Gitelman’s syndrome (Panel B), putativeloss-of-function mutations in the sodium–chloride transporterlead to decreased reabsorption of sodium chloride and in-creased reabsorption of calcium.

Lumen

A

Blood

K+

Na+

Na+

NCCT

Lumen

B

Blood

K+

Na+

Na+

Cl–

Cl–

Cl–

Ca2+

Mg2+ Na+

Na+

Cl–

Ca2+

Mg2+ Na+

Na+

Normal Kidney

Chloridechannel

Gitelman’s Syndrome

Chloridechannel

NCCT

Na+/K+–ATPase

Na+/K+–ATPase


1184 · Apr i l 15, 1999


although the persistence of hypercalcemia and hypo-calciuria after parathyroidectomy indicated that hy-perparathyroidism was not the primary physiologicdisturbance29,41 and that the set point for renal calci-um sensing might also be altered. In some infantsborn to consanguineous parents with familial hypo-calciuric hypercalcemia, severe hyperparathyroidism,characterized by hypercalcemia, failure to thrive, os-teopenia, and multiple fractures, develops soon afterbirth.29,42

Cloning studies identified the extracellular calci-um-sensing receptor, which is a G-protein–coupledreceptor of 1078 amino acids.43 In the kidney, thecalcium-sensing receptor is expressed on the baso-lateral surface of cells of the thick ascending limb,on the luminal surface of cells of the papillary col-lecting duct, and in other segments of the nephron.These are the sites at which hypercalcemia is knownto inhibit reabsorption of sodium chloride, calcium,and magnesium in the thick ascending limb (Fig. 3)and to inhibit the hydro-osmotic effect of vaso-pressin in the collecting duct. Genetic-linkage stud-ies mapped the gene for familial hypocalciuric hy-percalcemia to the same region of chromosome 3 asthe gene for the calcium-sensing receptor, strength-ening the evidence of a potential role of this gene asthe cause of familial hypocalciuric hypercalcemia andneonatal severe hyperparathyroidism. Mutations inthe gene for the calcium-sensing receptor were soondocumented, and over two dozen different muta-tions have now been identified in patients with theseconditions.

Approximately two thirds of the studied kindredswith familial hypocalciuric hypercalcemia have hadunique heterozygous mutations of the calcium-sens-ing receptor.42,44 These mutations cause the calcium-sensing receptor to respond only to higher-than-normal calcium concentrations, corresponding to arightward shift in the set point for calcium-depend-ent responses.44,45 Neonatal severe hyperparathyroid-ism is usually caused by homozygous mutations inthe children of consanguineous parents with hypo-calciuric hypercalcemia,44 but a few patients have hadnew heterozygous mutations.42

Gain-of-function mutations of the gene for thecalcium-sensing receptor cause hypocalcemia withnormal serum parathyroid hormone concentrations,a combination that suggests an abnormality in theset point of the calcium-sensing receptor. Expressionstudies confirmed that these mutations cause the re-ceptor to respond to lower-than-normal concentra-tions of calcium, corresponding to a leftward shift inthe dose–response curve for calcium-dependent re-sponses.45,46 Patients with these mutations also havehypercalciuria, and some have nephrocalcinosis andrenal impairment, raising the possibility that abnor-malities of the calcium-sensing receptor may con-tribute to idiopathic hypercalciuria.

MUTATIONS AFFECTING A

VOLTAGE-GATED CHLORIDE CHANNEL

In the past several decades syndromes have beendescribed that are characterized by various combina-tions of renal proximal tubular dysfunction, protein-uria, hypercalciuria, nephrocalcinosis, nephrolithiasis,renal failure, and rickets; these disorders have beenreferred to as Dent’s disease, X-linked recessive neph-rolithiasis with renal failure, X-linked recessive hypo-phosphatemic rickets, and low-molecular-weight pro-teinuria with nephrocalcinosis. Their relation to oneanother was made clear by the recent demonstrationthat all are caused by mutations affecting a chloridechannel.47 The spectrum of phenotypic features wasremarkably similar in the various syndromes, exceptfor differences in the severity of bone deformities andrenal impairment.47 For example, in Japan a nation-wide screening program for low-molecular-weightproteinuria led to the identification of very mild casesof this disease in asymptomatic schoolchildren.48

These X-linked syndromes49 should be viewed as vari-ants of one disease that for simplicity’s sake can becalled Dent’s disease, acknowledging Charles Dent,who in 1964 described two unrelated boys with hy-percalciuric rickets and proximal tubular dysfunction.50

Urinary loss of low-molecular-weight proteins isthe most consistent abnormality: it is present in allaffected males and in almost all female carriers of thedisorder.50,51 Other signs of impaired solute reab-sorption in the proximal tubule, such as renal glyco-suria, aminoaciduria, and phosphate wasting, are vari-able and can be intermittent. Hypercalciuria is an earlyand common feature. Hypokalemia occurs in somepatients. Urinary acidification is normal in over 80percent of patients, and when it is abnormal, the de-fect has been attributed to hypercalciuria or nephro-calcinosis.50-52 The disease apparently does not recurafter kidney transplantation.47

These phenotypic features indicate the presence ofproximal tubular dysfunction but do not suggest itspathophysiologic basis. However, mapping studieshave established linkage to the short arm of theX chromosome (Xp11.22).53 A chromosomal micro-deletion detected in one family led to mapping ofthe region and identification of a gene encoding avoltage-dependent chloride channel, ClC-5, that isexpressed predominantly in the kidney. A total of 35mutations have been identified to date in 46 fami-lies.47,54-56 Expression studies confirm that these mu-tations inactivate the chloride channel.54,56

Thus, positional cloning led to the identificationof a disease-causing gene whose physiologic func-tion was unknown. The gene is a member of a familyof genes encoding voltage-gated chloride channels.These genes include ClC-1, the gene for the principalmuscle chloride channel, which is mutated in Thom-sen’s and Becker’s myotonias, and ClC-Kb, one ofthe genes responsible for Bartter’s syndrome (Fig.



Volume 340 Number 15 · 1185

3D). ClC-5 is expressed in the subapical endosomesof the proximal tubule, where it may allow chlorideto enter the endosome and dissipate the positivecharge generated during acidification by the protonATPase.57 Impairment of this channel could limitendosomal acidification, thus causing defective reab-sorption of proteins, and might also lead to impairedreabsorption of other solutes if membrane proteinrecycling were altered.

It is not clear how this process could explain theincreased intestinal calcium absorption51 and highserum concentrations of 1,25-dihydroxyvitamin D inthis disorder,47 because the 1a-hydroxylase that cat-alyzes its formation from 25-hydroxyvitamin D is lo-cated in the mitochondria of proximal tubular cells.ClC-5 is expressed in the thick ascending limb ofHenle’s loop,57 which is a major site of renal calciumreabsorption. The role of this channel in the reab-sorption of calcium in the thick ascending limb re-mains to be established. Expression of ClC-5 hasalso been reported in the acid-secreting a-intercalat-ed cells of the collecting duct.57 The clinical or phys-iologic importance of this observation is uncertain,because the majority of patients with Dent’s diseasehave normal urinary acidification.47,50,51 However, inone pedigree, the initial description of the pheno-type was “hereditary distal renal tubular acidosis.”52

MUTATIONS ASSOCIATED WITH

X-LINKED HYPOPHOSPHATEMIC RICKETS

Albright et al. recognized that in some patients withrickets, the disease did not respond to normal dosesof vitamin D but did respond to large doses. Theycalled this condition “vitamin D–resistant rickets.”58

The most common form of this condition is associ-ated with hypophosphatemia, and its inheritance isX-linked.59 The hypophosphatemia is associated witha low threshold for renal tubular phosphate reabsorp-tion, with increased urinary phosphate excretion. De-fective proximal tubular reabsorption of phosphatein X-linked hypophosphatemic rickets would be ex-pected to stimulate the production of 1,25-dihy-droxyvitamin D, and yet serum 1,25-dihydroxyvita-min D concentrations are normal. As a consequence,urinary excretion of calcium is not increased andmay even be reduced. Thus, the disease may involvedefective regulation of the renal 1a-hydroxylase, inaddition to defective sodium-dependent phosphatetransport in the proximal tubule.

X-linked hypophosphatemic rickets was mapped tothe short arm of the X chromosome at Xp22.1, andthis led to the isolation of a gene that was mutatedin patients with X-linked hypophosphatemic rick-ets.60,61 This gene encodes a protein that shares ho-mologies with endothelin-converting enzyme, theKell antigen, and a neutral endopeptidase. The geneis therefore referred to as PHEX (phosphate-regulat-ing gene with homologies to endopeptidases on the

X chromosome). The gene product is a type II in-tegral membrane glycoprotein that has endopepti-dase activity.62 In humans this protein is expressed inkidney, bone, and other tissues.62 Neutral endopep-tidase and endothelin-converting enzyme are in-volved in the inactivation and activation of hor-mones, respectively. The physiologic function of thePHEX protein may be to activate a hormone that pro-motes phosphate retention or inactivate a phospha-turic hormone.61 Evidence of the existence of a phos-phate-regulating hormone called “phosphatonin”63

is based largely on studies of patients with mesen-chymal tumors who have hypophosphatemic osteo-malacia (oncogenous osteomalacia). These patientshave metabolic abnormalities that are indistinguish-able from those in patients with X-linked hypophos-phatemic rickets. Resection of the tumor, which isusually benign, corrects the metabolic abnormalities.64

A related phenotype, hereditary hypophosphatemicrickets with hypercalciuria, differs from X-linked hy-pophosphatemic rickets in that affected patients havehigh serum 1,25-dihydroxyvitamin D concentrations,as would be expected if defective phosphate reab-sorption was the only abnormality and 1a-hydroxyl-ation of vitamin D was normally responsive to cellu-lar phosphate depletion. Thus, unlike patients withX-linked hypophosphatemic rickets, these patientshave increased intestinal absorption of calcium andhypercalciuria.65 The inheritance in the Bedouinkindred in which the disease was identified, in whichthere was a high degree of consanguinity, appearedto be autosomal recessive, and thus it seems unlikelythat the X-linked genes PHEX and ClC-5 are in-volved. The underlying defect could represent a lossof function of the sodium-dependent renal phos-phate transporter in the apical membrane, which isencoded on chromosome 5. The characteristics ofheterozygous females with this disorder resemblethose of patients with idiopathic hypercalciuria,66

and thus the nature of the molecular defect in thisdisease may be relevant to the understanding of id-iopathic hypercalciuria.

CONCLUSIONS

Each of the syndromes reviewed demonstrates thepower of molecular and genetic techniques in defin-ing the underlying pathophysiology of human disease.The candidate-gene approach was directly applied inthe example of Liddle’s syndrome and pseudohy-poaldosteronism type I. Dent’s disease and X-linkedhypophosphatemic rickets provide contrasting ex-amples in which genetic-linkage studies identifiedpreviously unknown candidate genes and thereby il-luminated the physiologic role of newly describedproteins. Studies of Bartter’s and Gitelman’s syn-dromes demonstrate that phenotypic variations maybe attributed to different genetic loci, all of whichcode for proteins that participate in an integrated


1186 · Apr i l 15, 1999


physiologic process (i.e., the reabsorption of sodiumchloride in the thick ascending limb and distal con-voluted tubule). Future advances may include theidentification of additional genes to explain geneticheterogeneity, as occurs in Bartter’s syndrome, aswell as the identification of genes that modulatephenotypic heterogeneity in the variable phenotypein Dent’s disease, for example. Polymorphisms in thegenes for the transporters that have less severe func-tional consequences may explain more common trans-port disorders, such as idiopathic hypercalciuria, di-uretic-induced renal potassium wasting, and evensome forms of low-renin hypertension.

Supported by grants from the National Institutes of Health (DK46838,to Dr. Scheinman, and DK53161, to Dr. Warnock), a grant from the NorthAtlantic Treaty Organization (CGR950114, to Drs. Scheinman and Thakker),funds from the Medical Research Council (to Dr. Thakker), and fundsfrom the Alabama Kidney Foundation (to Dr. Guay-Woodford).

We are indebted to Dr. Peter Friedman for his helpful comments.

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