Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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40 Reed and Gitomer

mutations in a new gene ATP6NB1, which encodes a further subunit of the VH

-ATPase

were identified in affected kindreds (68). Further mutations in both the ATP6B1 and

ATP6NB1 genes have recently been reported (69). In addition to elucidation of the

specific gene defect associated with various forms of dRTA, molecular studies have also

provided new insight into the mechanism of acid secretion in the kidney underlining the

important synergism between molecular and cellular biology.

Hypophosphatemia

Renal phosphate leak resulting in hypophosphatemia leads to elevation of 1,25(OH)

vitamin D with consequences of increased intestinal calcium absorption, parathyroid

suppression, and hypercalciuria. The type 2a sodium-phosphate cotransporter (NPT2a)

is localized in the apical membrane of the renal proximal tubular cells where it represents

the rate-limiting step in phosphate resorption in the kidney and is consequently a can-

didate gene for the defect in hypophosphatemia (70). Screening of the NPT2a gene in 20

patients with urolithiasis and bone loss revealed two mutations in the NPT2a gene

(71). Expression of the mutant protein in Xenopus oocytes revealed diminished sodium

dependent phosphate uptake in oocytes expressing the mutant protein (71). Mutations in

the NPT2a gene have been ruled out in two other forms of familial hypophosphatemia—

X-linked hypophosphatemic rickets, which is associated with mutation of an endopep-

tidase on the X chromosome PHEXgene(72),and autosomal dominant hereditary rickets,

which is associated with mutation of the fibroblast growth factor 23 gene (73).

Other Stone Diseases Related to Hypercalciuric Nephrolithiasis

Mutation of the calcium-sensing receptor (CASR) has been associated with several

familial syndromes related to hypercalciuria with stone formation. The CASR is a plasma

membrane G protein-coupled receptor that is expressed in the parathyroid-producing

chief cells of the parathyroid gland and the kidney tubule-lining cells. PTH secretion and

renal cation handling are modified through changes in Ca

concentration detected by

the CASR (74). The gene encoding the CASR (CASR) has been mapped to chromosome

3q13.3-q21 by Janicic et al. and is made up of six exons (75). Multiple mutations have

been described in the CASR and were recently reviewed by Hendy (76). Activating

mutations in the CASRhave been described in familial hypocalcemia with hypercalciuria

(76,77). Pearce et al. concluded that depending on the site of the mutation in the CASR

gene it is possible to modify the response of the CASR, effectively changing the set point

for Ca

sensing and secretion of parathyroid hormone (77). An inactivating mutation in

the cytoplasmic tail of the CASR was recently described in a Swedish family with

hypercalciuric hypercalcemia (78).

RIMARY HYPEROXALURIA TYPE 1

Primary hyperoxaluria type1 (PH1) is a rare autosomal recessive disorder. In North

America it accounts for 0.7% of end-stage renal disease in children, whereas the preva-

lence in Mediterranean countries is much higher; in Tunisia it accounts for 13.5% of

children with end stage renal disease (79). The disease is caused by a deficiency of the

peroxisomal enzyme AGT (80). AGT catalyzes the conversion of glyoxlate to glycine.

Functional deficiency of the enzyme allows glyoxylate to be oxidized to oxalate in the

peroxisome by glycolate oxidase or by lactate dehydrogenase in the cytoplasm.

Glyoxylate is also reduced to glycolate by glyoxylate reductase in the cytoplasm

Chapter 3 / Genetics of Stone Disease 41

(Fig. 1). The primary clinical manifestations of the disorder are related to increased

excretion of oxalate and glycolate. Oxalate is excreted by the kidney and the increased

concentration of oxalate results in formation of insoluble calcium oxalate (CaOx) de-

posits in the kidney (nephrocalcinosis) or urinary tract resulting in urolithiasis or neph-

rolithiasis, leading to eventual renal failure. Following renal failure, systemic oxalosis

occurs with CaOx deposition throughout the body. The gene encoding AGT (AGXT)

was mapped to chromosome 2q 36-37 and comprises 11 exons, which encode a 1600-

bp cDNA (81). To date more than 30 separate mutations have been identified in AGXT

associated with PH1 (82). There is considerable heterogeneity of phenotype associated

with PH1, the most common presentation occurring in infancy with progression to renal

failure in childhood or early adulthood. The spectrum of disease ranges from extreme

cases of renal failure during infancy to renal failure in late adulthood (83). Similar

heterogeneic diversity exists at the enzyme level in PH1. Some patients have no enzy-

matic or immunoreactive AGT, whereas others retain 30–50% of the normal catalytic

activity. In these patients AGT activity falls within the range of activity associated with

heterozygotes (84). The variability of AGT activity in PH1 has made clinical diagnosis

Fig. 1. Metabolic defect associated with PH1. AGT, alanine glyoxylate aminotransferase.

GRHPR, glyoxylate reductase/

-glycerate dehydrogenase/hydroxypyruvate reductase. LDH,

lactate dehydrogenase. Elevated metabolites are indicated in large type.

42 Reed and Gitomer

based on enzyme assay difficult. Numerous mutations and polymorphisms have been

identified in AGXT. The most common mutations are associated with amino acid sub-

stitutions G170R and I244T and account for 30% and 9%, respectively, of the disease

alleles encountered (84,85). Many polymorphisms have also been described, the most

common being the amino acid substitutions P11L and I340M, which segregate with a

frequency of 20% in normal European and North American populations (84,86). A

unique mistargeting defect is associated with the occurrence of the P11L polymorphism

and the G170R mutation. The P11L polymorphism creates a weak mitochondrial target-

ing sequence the strength of which increases in the presence of the G170Rmutation(86).

In patients expressing 30–50% of normal enzyme activity, disease is associated with

mistargeting of the enzyme to the mitochondrion instead of the peroxisome in hepato-

cytes. Lumb et al. have examined the synergism between the P11L polymorphism and

four of the most common disease-associated mutations using an in vitro expression

system (82). They demonstrated a threefold reduction in specific activity of the enzyme

associated with the P11L polymorphism. Expression of AGT containing the G41R,

F152I, G170R, or I244T mutations resulted in a soluble and catalytically active enzyme.

However, in the presence of the P11L polymorphism all mutations resulted in protein

destabilization and aggregation into inclusion bodies in the Escherichia coli expression

system (82). They also demonstrated that the G82E mutation abolished enzyme activity

by interfering with cofactor binding. Despite the fact that the kidney is the primary organ

affected by PH1, liver transplantation is required for cure of the disease as AGT is a

hepatic enzyme. In PH1 associated with a mistargeting defect, liver transplantation

allows replacement of the enzyme within the correct organ and appropriate peroxisomal

expression results within the transplant. Limited therapeutic benefit has been associated

with renal transplant alone owing to persistence of the liver defect, which allows for-

mation of further CaOx precipitates in the transplanted kidney (5). In a worldwide study

of the outcome of PH1, Cochat demonstrated 33% morbidity associated with patients

undergoing transplantation as compared with 71% of patients without transplantation

(87).

RIMARY HYPEROXALURIA TYPE 2

Primary hyperoxaluria type 2 (PH2) is a rare monogenic disorder, which is inherited

as an autosomal dominant trait. The disease is caused by a deficiency of the enzyme

glyoxylate reductase (GRHPR) (also called

D-glycerate dehydrogenase or hydroxypyru-

vate reductase) (88), which catalyzes the conversion of glyoxylate to glycolate (Fig. 2).

When the enzyme is deficient, more glyoxylate is oxidized to oxalate. Glyoxylate reduc-

tase also catalyzes the reduction of hydroxypyruvate to

D-glycerate; in PH2 hydroxypy-

ruvate is reduced to

L-glycerate. Clinically PH2 is characterized by increased oxalate and

L-glycerate excretion. The presence of L-glycerate and absence of glycolic acid in the

urine serves to distinguish PH2 from PH1. Increased oxalate excretion results in neph-

rolithiasis and nephrocalcinosis and can progress to renal failure although PH2 generally

has a less severe phenotype than PH1 (89). The cDNA encoding the GRHPR has been

identified as an 1198-bp clone made up of nine exons, which encodes a 328 amino acid

protein (90). The corresponding gene was mapped to chromosome 9cen within the

reference interval D9S1874-D9S273 (91). Cramer et al. used a combination of single-

stranded conformational polymorphism and sequence analyses to identify a single-nucle-

otide deletion in exon 2 of the GRHPR gene in four patients with PH2 (92). The deletion

results in a frameshift mutation and protein truncation. Five additional mutations were

Chapter 3 / Genetics of Stone Disease 43

identified in 11 patients with PH2 by Webster et al., confirming the association between

the GRHPR gene and PH2 (92).

CYSTINE-CONTAINING STONES

Cystinuria, one of the inborn errors of metabolism first discussed by Garrod (93), is

an autosomal recessive or incompletely recessive familial transport disorder, which is

characterized by an exaggerated renal excretion of cystine and the dibasic amino

acids arginine, lysine, and ornithine (reference 94 and references cited within). Because

of the low solubility of cystine in urine, the increased excretion results in the formation

of cystine stones (95). Clinically, a patient who excretes >250 mg cystine/g creatinine/d

is classified as being cystinuric (96).

Fig. 2. Metabolic defect associated with PH2. GRHPR, glyoxylate reductase/d-glycerate dehy-

drogenase/hydroxypyruvate reductase. LDH, lactate dehydrogenase . Elevated metabolites are

indicated in large type.

44 Reed and Gitomer

Phenotypic Subtyping of Cystinurics

Since the initial studies of Rosenberg, et al. (97,98), cystinuria has been classified into

subgroups based on physiological observations of affected individuals and obligate

carriers of the disease (Table 3). Type I cystinuria is inherited in an autosomal recessive

manner, with homozygous patients excreting increased amounts of cystine and other

dibasic amino acids and heterozygous carriers having normal urinary amino acid profiles

(96). Cystinuria types II and III are inherited in an incompletely recessive manner

(97,98)

with heterozygotes having elevated, although usually not pathological, urinary excre-

tion of dibasic amino acids. The observed aminoaciduria is generally more pronounced

in type II heterozygotes than type III heterozygotes, although there is overlap between

the two subgroups (97,98). Intestinal handling of dibasic amino acids further differen-

tiates the three subtypes of cystinuria. Intestinal biopsies from type III, but not type I,

cystinurics exhibit active transport of cystine, lysine, and arginine, whereas biopsies

from type II cystinurics exhibit only a slight active transport of cystine and no transport

of lysine

(97). In addition, an oral cystine load in patients with type III cystinuria will

cause a temporal increase in plasma cystine concentration, but not in patients with type

I or II presentations (97,98).

Renal Cystine Transporters

The increase in urinary dibasic amino acids observed in cystinuria is a consequence

of a defect in the renal reuptake mechanism(s) for these amino acids because the plasma

concentrations remain normal or slightly below normal (99). Two renal transport sys-

tems for cystine have been described. One of the transporters, located in the proximal

straight tubule (100), has a high affinity for cystine with a relatively low maximum rate

of transport, whereas the other transporter, located in the proximal convoluted tubule

(101), has a low affinity for cystine and a high maximum rate of transport. The high

affinity system has an apparent K

for cystine of 12 µM and a maximum transport

velocity of 19 µmol cystine/L intracellular water/min, (102) and has been shown to

catalyze hetero-exchange of dibasic amino acids with neutral amino acids(103). The low

affinity transporter has a K

for cystine of 550 µM and a 13-fold greater maximum

velocity than the high affinity system (V = 256 µmol cystine/L intracellular water/min)

(102). The two transporters also differ in their specificity for dibasic amino acids and

their dependence on Na

. The high affinity system will also transport arginine, lysine,

Table 3

Phenotypic Differentiation of Cystinuric Subtypes

Active transport of dibasic

amino acids in intestinal

Change in plasma

Cystinuric

biopsies from homozygotes

after cystine load in Urinary dibasic amino

subtype cys

lys arg homozygotes acids in heterozygotes

I – – – no change normal

II ± –nd

no change elevated

III + + + increase elevated

Adapted from 97.

nd = not determined.

Chapter 3 / Genetics of Stone Disease 45

and ornithine, and does not require Na

(102,104), whereas the low affinity transporter

is specific for cystine (102) and is Na

-dependent (104) with an apparent K

for Na

36 mM (102). Because only the high affinity transporter also transports arginine, lysine,

and ornithine, it has been proposed that this is the transporter system most likely involved

in cystinuria (105).

Genes Coding for Renal Cystine Transporters

Of the two cystine transporters described biochemically, only the high-affinity/low-

capacity transporter has been cloned (106–108). The transporter is a heterodimer

(109,110) consisting of a heavy subunit and a light subunit. There are a number of recent

reviews that extensively describe these proteins and their involvement with cystinuria

(111–114).

The heavy subunit (rBAT) is coded for by the SLC3A1 gene (106,107) located on

chromosome 2p (8). The structure of the gene within the genomic DNA consists of 10

exons(115,116). More than 40 mutations (seereferences112, 113 and references therein)

within this gene that have been identified and in all instances in which the patients have

been subtyped the SLC3A1 mutations have been shown to occur only in type I cystinurics

(117–119).

The light subunit b

(0,+)

AT is coded for by the SLC7A9 gene (108), which is located

on chromosome 19q (120–122). The gene consists of 13 exons (108) and 35 mutations

have been reported in this gene. However, unlike the SLC3A1gene, mutations within this

gene have been found in all subtypes of cystinuria (108).

Taken together identified mutations within these two genes can account for approx

80% of cystinuric patients studied. Whether the other approx 20% of patients have

disease causing mutations within unscreened portions of the SLC3A1 and SLC7A9

genes (i.e., the introns and promoter regions) or the disease is caused by mutations in an

as yet unidentified gene (123) remains to be determined.

STONE FORMATION CAUSED

BY ABERRATIONS IN NUCLEOTIDE METABOLISM

The last group of stone disease to be discussed is all related because the stones formed

are all composed of products of purine nucleotide metabolism (Fig. 3). Stone formation

has been shown to be caused by either direct defects in the enzymes of nucleotide

metabolism, as in the formation of xanthine, 2,8-dihydroxyadenine, and uric acid stones,

or indirect effects of the urinary environment, such as uric acid stones in which a severe

decrease in urinary pH below 5.5 leads to stone formation.

Uric Acid Stones

PARTIAL HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE DEFICIENCY

Lesch–Nyhan syndrome (LNS, 124, OMIM 300322) and Kelley–Seegmiller syn-

drome (KSS, 125, OMIM 300323) are X-linked recessive diseases that result from

mutations in hypoxanthine guanine phosphoribosyltransferase (HPRT). The two syn-

dromes differ in the amount of residual HPRT activity with LNS having <1.5% wild-type

HPRT activity and KSS having at least 8% wild-type HPRT activity (126). Even though,

the clinical presentation of LNS (abnormal metabolic and neurologic symptoms) is

much more severe than KSS, uric acid stones are uncommon in LNS, whereas they are

46 Reed and Gitomer

often one of the sole presenting symptoms of KSS (126). Additionally, the occurrence

of partial HPRT deficiency in patients presenting with uric acid stones and/or gout is

quite rare with Yu et al. (127) reporting only seven cases (five from the same family) of

partial HPRT deficiency out of 425 cases examined.

The gene coding for HPRT is located at the chromosomal locus Xq26-q27 (128) and

contains nine exons spanning a region of 44 kb (129). HPRT, part of the purine nucle-

otide salvage pathway, catalyzes the condensation of PRPP with either guanine or hypo-

xanthine to form GMP and IMP, respectfully (Fig. 3). Diminished activity of the enzyme

leads to increased flux through the xanthine dehydrogenase catalyzed reaction and thus

increased uric acid formation. A large number of mutations have been reported in the

HPRT gene (126); however, in most instances as stated previously, only those mutations

causing a less severe decrease in enzyme activity are associated with uric acid stone

formation (126).

HOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE 1 SUPERACTIVITY

Greatly increased activity of phosphoribosylpyrophosphate synthetase (PRPPS) has

been shown to be associated with increased uric acid production, gout, and uric acid stone

formation (130). PRPPS catalyzes the formation of PRPP from the condensation of ATP

and ribose 5-P (Fig. 3). The increase in enzyme activity has been shown to be caused by

either an insensitively to allosteric regulation by ADP and GDP (131), which is present

in the wild type enzyme, or an overexpression of the enzyme protein (132). Two isoforms

of PRPPS have been identified—PRPPS 1 and PPRPS 2. The two enzymes are located

on opposite arms of the X chromosome with the PRPPS 1 locus at Xq22-q24 and the

Fig. 3. Interrelationship of the purine salvage pathways of guanine, adenine, and hypoxanthine.

Compounds underlined form renal stones when appropriate genetic defects are present (see text

for details). PRPP, 5-phosphoribosyl-1-pyrophosphate; HPRT, hypoxanthine guanine phos-

phoribosyltransferase; XDH, xanthine dehydrogenase; APRT, adenine phosphoribosyltrans-

ferase; PRPPS, phosphoribosylpyrophosphate synthetase.

Chapter 3 / Genetics of Stone Disease 47

PRPPS 2 locus at Xp22.3-p22.2 (133). To date only mutations in PRPPS 1 have been

associated with increased enzyme activity and uric acid stone formation (134). A conse-

quence of the superactivity of PRPPS 1 is an increase in the de novo and salvage pathways

of purine, pyrimidine, and pyridine nucleotides, which in turn leads to increased uric acid

production (134).

DIOPATHIC INHERITED URIC ACID STONE FORMATION

In the early 1960s there were two reports of familial uric acid nephrolithiasis that

were inherited in an autosomal dominate manner (135,136). These individuals did not

have gout or hyperuricemia but did exhibit an excessively low urinary pH (<5.5) and

an early onset of stone disease (135,136). Whether this is a defect directly involving

either uric acid synthesis or transport, or a defect in the regulation of urinary acidifica-

tion is not known. Of interest is the recent report of a linkage analysis study in a small,

isolated founder population of a Sardinian village with an increased prevalence of uric

acid stone formation relative to Western populations. The authors identified two chro-

mosome loci with evidence of linkage for susceptibility genes for uric acid stones. The

strongest linkage was found at 10q21-q22, where a lod score of 3.07 was obtained for

chromosomal marker D10S1652. In addition suggestive, but not definitive, evidence

was obtained for linkage at chromosomal locus 20q13.1-q13.3 using multipoint non-

parametric analysis (137). However, screening of the two regions for likely candidate

genes for uric acid lithiasis using data from the Human Genome Project yielded no

likely candidate genes.

Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT) deficiency results in the increased for-

mation and urinary excretion of 2,8-dihydroxyadenine (138) as a consequence of a

defect in the salvage pathway for the conversion of adenine to AMP (Fig. 3). The low

solubility of 2,8-dihydroxyadenine leads to stone formation. APRT deficiency is inher-

ited in an autosomal recessive manner (138) and the chromosomal loci for the gene

coding for APRT is 16q22.2-q23.2 (139). The gene for APRT consists of five exons

spanning 2.5 kb of genomic DNA (140). A number of mutations in the gene have been

identified (141) and based on the residual amount of enzyme activity APRT deficiency

has been divided into two subtypes. Type-1 patients, who are predominantly Caucasian,

have no residual enzyme activity (142) whereas type-2 patients, who are predominantly

Japanese, have up to 25% residual enzyme activity (143). Both the clinical and enzy-

matic presentations of APRT deficiency are heterogeneous and a number of individuals

with mutations are asymptomatic (144).

Xanthinuria

Xanthinuria results from a deficiency in the activity of xanthine dehydrogenase (XDH;

see Reference 145) that leads to over excretion of xanthine and, as a consequence of its

low solubility, xanthine stone formation. Xanthinuria has been divided into two subtypes

based on enzyme deficiencies. Type-1 xanthinuria is the result of the sole deficiency of

XDH, which catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric

acid (see Reference 145; Fig. 3). In type-2 xanthinuria, XDH deficiency is coupled to

aldehyde oxidase deficiency (146). It has been proposed that the defect in type-2

xanthinuria is not caused by mutations in either the XDH or AO genes but is caused by

48 Reed and Gitomer

disruption of the mechanism by which an essential sulfur atom is inserted into the active

sites of both enzymes (146). Type-1 patients can metabolize allopurinol, whereas type-

2 patients cannot (147). It should be noted that xanthinuria, like hyperoxaluria, is prima-

rily a hepatic disease because XDH is found predominately in the liver and as such, as

with hyperoxaluria, specific attention should be given to the hepatic defect when treating

the presenting renal disease.

The gene coding for XDH has been localized to the chromosomal locus 2p23-p22

(148) and has been to shown to consist of 36 exons spanning 60 kb of genomic DNA

(149). Only three unique mutations in the gene have been reported (150).

CONCLUSION

Genetic studies have greatly facilitated our understanding of the underlying disease

process in numerous stone-forming disorders. However, sometimes identification of a

specific gene defect does not unlock the door to the understanding of the pathophysiol-

ogy of a disease process. Once a gene has been identified often the most complex

problem is the elucidation of the biochemical role of the related protein. Given the

availability of suitable families for genetic study and careful clinical phenotype evalu-

ation genome-wide screening can be undertaken fairly rapidly. Characterization of a

mutant protein may often require intricate and time-consuming biochemical and physi-

ological studies. In conclusion one significant benefit arising from identification of

disease associated genes is the option of genetic testing as an aid to clinical diagnosis.

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