• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Dent Disease

Includes: Dent Disease 1, Dent Disease 2

, MD, , MD, , MD, and , MD.

Author Information
, MD
Mayo Clinic
Rochester, Minnesota
, MD
Mayo Clinic
Rochester, Minnesota
, MD
New York University School of Medicine
New York, New York
, MD
Mayo Clinic
Rochester, Minnesota

Initial Posting: .

Summary

Disease characteristics. Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD). Males younger than age ten years may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. Rickets or osteomalacia are occasionally observed, and mild short stature, although underappreciated, may be a common occurrence. Disease severity can vary within the same family. Males with Dent disease 2 (caused by mutations in OCRL) are at increased risk for intellectual disability. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely if ever develop CKD.

Diagnosis/testing. The diagnosis is based on renal findings and/or a family history consistent with X-linked inheritance. A mutation in CLCN5 accounts for approximately 60% of those with Dent disease (known as Dent disease 1); a mutation in OCRL accounts for approximately 15% of those with Dent disease (known as Dent disease 2).

Management. Treatment of manifestations: The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD). No randomized controlled trials have been performed. Although thiazide diuretics can decrease urinary calcium excretion in boys with Dent disease, side effects limit their use. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in children with proteinuria to prevent or delay further loss of kidney function is unclear. Renal replacement therapy is necessary in those with ESRD.

Prevention of secondary complications: Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion. Growth failure may be treated with human growth hormone without adversely affecting kidney function.

Surveillance: Monitor at least annually urinary calcium excretion, renal function (glomerular filtration rate [GFR]), and the parameters used to stage CKD (i.e., blood pressure, hematocrit/hemoglobin, and serum calcium and phosphorous concentrations). Monitor more frequently when CKD is evident.

Agents/circumstances to avoid: Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents).

Evaluation of relatives at risk: Clarify the genetic status of at-risk male relatives by either molecular genetic testing if the mutation in the family is known or measurement of urinary excretion of low molecular weight proteins (LMWPs).

Genetic counseling. Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be a carrier of the mutation. If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%: males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be significantly affected. Affected males pass the disease-causing mutation to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family has been identified.

Diagnosis

The diagnostic criteria for Dent disease include the three criteria below in the absence of other known causes of proximal tubule dysfunction [Hoopes et al 2004]. Note: A possible diagnosis of Dent disease is considered if LMW proteinuria and at least one other criterion are present.

1.

LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often ten times) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin.

Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors’ knowledge no known cases of Dent disease have been missed using this screening method, however, its use is cautioned since it is not stable in even minimally acidic urine [Davey & Gosling 1982]; thus, theoretically false negative results are possible.

2.

Hypercalciuria

  • Adults (age >18 years). >4.0 mg calcium (0.1 mmol)/kg in 24 hours or >0.25 calcium/creatinine mg/mg (0.57 mmol/mmol) in spot urine.
  • Children. See Table 1 for 95th percentile calcium/creatinine mg/mg reference values in random urine collections.
3.

At least one of the following

  • Nephrocalcinosis (diffuse renal calcification)
  • Nephrolithiasis (kidney stones) (composed of calcium oxalate and/or calcium phosphate)
  • Hematuria (microscopic or macroscopic blood in the urine)
  • Hypophosphatemia (low blood phosphorous concentration)
  • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is less than the normal limits for age
  • Family history consistent with X-linked inheritance

In 75% of males who meet the above criteria, a mutation in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2) confirms the diagnosis.

Table 1. Calcium/Creatinine (mg/mg) Reference Values in Children (age <18 yrs)

Age (yr)95th percentile
0-1<0.81
1-2<0.56
2-3<0.50
3-5<0.41
5-7<0.30
7-10<0.25
10-14<0.24
14-17<0.24

In random urine collections

Matos et al [1997]

Testing

Renal biopsy. Findings consistent with Dent disease include nephrocalcinosis, interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS) and/or focal global glomerulosclerosis (FGGS) [Copelovitch et al 2007, Frishberg et al 2009].

Molecular Genetic Testing

Genes. Mutations in two genes are known to cause Dent disease: CLCN5 (Dent disease 1) and OCRL (Dent disease 2). Mutation in CLCN5 accounts for approximately 60% of those with Dent disease; mutation in OCRL accounts for approximately 15% of those with Dent disease (Table 2). (See Table A. Genes and Databases for chromosome locus and protein name for these genes.)

Evidence for further locus heterogeneity. Approximately 25% of those with Dent disease do not have an identified disease-causing mutation in CLCN5 or OCRL, suggesting additional genetic heterogeneity [Hoopes et al 2004, Hoopes et al 2005].

Table 2. Summary of Molecular Genetic Testing Used in Dent Disease

Gene Symbol
(Phenotype)
Proportion of Dent Disease Caused by Mutation of This Gene 1Test MethodMutations Detected
CLCN5
(Dent disease1)
60%Sequence analysisSequence variants 2
Deletion / duplication analysis 4Exonic, multiexonic, or whole-gene deletions / duplications 5, 6
OCRL
(Dent disease 2)
15%Sequence analysisSequence variants 2, 3
Deletion / duplication analysis 4Exonic, multiexonic, or whole-gene deletions 5, 7

1. Claverie-Martin et al [2010]

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Lack of amplification by PCRs during sequence analysis can suggest a putative deletion in a male; confirmation may require additional testing by deletion/duplication analysis.

6. Unknown

7. One deletion of exons 3 and 4 was reported [Hichri et al 2011].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband (i.e., the first person in a family to be evaluated). Investigators of the Rare Kidney Stone Consortium have devised the following diagnostic strategy to help determine when to suspect and confirm a diagnosis of Dent disease. The criteria to confirm a diagnosis are those of Hoopes et al [2004].

For probands with pathologic proteinuria (defined as trace or greater protein by dipstick OR >0.2 mg protein / mg creatinine OR >100 mg protein/day) without a known cause (i.e., a known glomerular disease other than focal sclerosis; see Testing, Renal biopsy regarding exceptions):

1.

Measure urinary LMWP

2.

In the presence of LMW proteinuria, evaluate for:

  • Hypercalciuria
  • Nephrolithiasis or nephrocalcinosis
  • Hypophosphatemia with or without rickets
  • Family history of Dent disease
  • Family history of ESRF or proteinuria consistent with X-linked inheritance
3.

Perform molecular genetic testing in probands who have LMW proteinuria and at least one of the findings listed in 2.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.

Most heterozygous females do not have severe disease manifestations except in the (rare) case of one of the following findings:

See Symptomatic Females.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

In the early stages of Dent disease children (usually about age <10 years) may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, both of which are usually asymptomatic [Claverie-Martin et al 2010].

LMW proteinuria and/or hypercalciuria can be accompanied by stone disease or nephrocalcinosis, and less frequently by other manifestations of proximal tubular dysfunction including aminoaciduria, phosphaturia, and glycosuria [Hodgin et al 2008]. The disease may also be accompanied by rickets or osteomalacia, short stature, and growth retardation [Bökenkamp et al 2009]. Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact PTH [Scheinman 1998]. In patients hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption.

Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade or later [Wrong et al 1994, Lloyd et al 1997]. Of note, deterioration of renal function can occur even in the absence of nephrocalcinosis. Disease severity can vary even within the same family.

Short stature is common, although not usually profound in Dent disease 1. In one series height was -0.58 SD of the age-appropriate mean value for Dent disease 1 and -2.10 SD for Dent disease 2 [Bökenkamp et al 2009].

Dent Disease 1 (caused by mutation of CLCN5)

The phenotypic findings in Dent 1 vary.

Scheinman et al [2000] reported a family in which all affected individuals had the same CLCN5 missense mutation (c.1517G>A; p.Gly506Glu) and the Dent disease phenotype ranged from severe in several members to isolated hypercalciuria without proteinuria, nephrocalcinosis, or chronic kidney disease (CKD) in one. It is not currently known how often an individual with a CLCN5 mutation manifests only asymptomatic hypercalciuria and/or proteinuria without developing CKD.

Some individuals with mutation in CLCN5 and a family history of Dent disease developed ESRD with proteinuria, but without other typical features of Dent disease (i.e., kidney stones, nephrocalcinosis, or bone disease) [Copelovitch et al 2007, Frishberg et al 2009]. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) and focal global glomerulosclerosis. The findings in these individuals illustrate that the spectrum of Dent disease includes persons with proteinuria and a biopsy consistent with FSGS and that the diagnosis is only considered when evaluations for LMW proteinuria and/or hypercalciuria are performed.

It is currently unclear if Dent disease will be diagnosed among a larger number of individuals with clinical FSGS.

Dent Disease 2 (caused by mutation of OCRL)

To date, about 25 males with Dent disease 2 have been reported.

The males in the initial report of Dent disease 2 exhibited none of the classic extrarenal symptoms of Lowe syndrome, an allelic disorder, which is characterized by congenital cataracts, hypotonia and delayed motor milestones, intellectual disability, and renal tubular involvement that leads to bone disease and growth retardation [Hoopes et al 2005]. Although males with classic Lowe syndrome have a renal phenotype similar to that of Dent disease, the tubular dysfunction is somewhat different:

  • Tubular acidosis, one of the cardinal signs of Lowe syndrome, is rare in Dent disease.
  • Features of Fanconi syndrome (amino aciduria, glucosuria, renal tubular acidosis) are observed more frequently in Lowe syndrome than in Dent disease.
  • Hypercalciuria, nephrocalcinosis, and nephrolithiasis are common in Dent disease but rare in Lowe syndrome.

Given the finding of OCRL mutations in about 15% of individuals with Dent disease, it has been suggested that mutations in OCRL are associated with a phenotypic continuum along a spectrum that ranges from Lowe syndrome at the severe end (see Genetically Related Disorders) to Dent disease 2 at the mild end.

In general it appears that about 6/11 of males with an OCRL mutation and a Dent phenotype have mild intellectual disability, whereas cataracts are rare and renal tubular acidosis has not generally been observed [Hoopes et al 2005, Shrimpton et al 2009].

  • Males with OCRL mutations who have typical findings of Dent disease (low molecular weight proteinuria, hypercalciuria, amino aciduria) have been observed to have mild intellectual disability [Hoopes et al 2005, Lozanovski et al 2011, Tasic et al 2011]. Unlike the renal disease in Lowe syndrome, the proximal tubular dysfunction and renal tubular acidosis observed in these individuals are not severe enough to require bicarbonate therapy [Hoopes et al 2005].
  • Within a family some affected individuals had mild intellectual disability while others did not [Hoopes et al 2005].
  • In a cohort from Germany, elevated muscle enzymes (LDH, CPK) were observed in about half of males with an OCRL mutation and a Dent phenotype, while intellectual disability was observed in only one of 21 affected males [Utsch et al 2006].
  • In a cohort from Korea, two of 12 males with a Dent phenotype had an OCRL mutation; one of these had mild developmental delay and elevated muscle enzymes, while the other did not. All seven males with the Lowe syndrome phenotype had an OCRL mutation. Urine B2 microglobulin excretion was increased in males with an OCRL mutation (Dent disease or Lowe syndrome phenotype), while renal tubular acidosis was present in all males with Lowe syndrome, but not in males with Dent disease caused by either an CLCN5 or an OCRL mutation [Cho et al 2008].

Symptomatic Females

As a result of X-chromosome inactivation (in which the X chromosome with the normal allele is by chance inactivated in a disproportionately large number of cells), females who are heterozygous for a mutation in CLCN5 or OCRL are mosaic for these mutations. There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have genetic testing [Wrong et al 1994].

Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a disease-causing CLCN5 or OCRL mutation on the remaining X chromosome).

Although not reported in the literature, a female with biallelic mutations in CLCN5 or OCRL (inherited from a carrier mother and an affected father) would be predicted to manifest clinically significant kidney disease.

Genotype-Phenotype Correlations

CLCN5. Genotype-phenotype correlations have yet to be established.

OCRL. It has been suggested that mutations in OCRL are associated with a phenotypic continuum along a spectrum that ranges from Lowe syndrome at the severe end (see Genetically Related Disorders) to Dent disease 2 at the mild end (see Clinical Description).

Note: Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered protein reabsorption) and Dent disease is similar, it is generally milder in Dent disease. Of note, this milder Dent disease phenotype could not be attributed to lesser protein expression or enzyme activity.

Frameshift and nonsense OCRL mutations associated with Dent disease 2 have been mapped to exons different from those causing Lowe syndrome [Hichri et al 2011]; however, missense, splicing, and in-frame deletion OCRL mutations that cause these two disorders do not map exclusively to specific gene regions.

  • Frameshift and nonsense mutations associated with Dent disease 2 are in the first seven exons. Missense mutations associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain.
  • Frameshift and nonsense mutations associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [Tosetto et al 2009, Hichri et al 2011].

Prevalence

To date about 250 affected families have been reported [Devuyst & Thakker 2010]. However, the wide variability of clinical presentation in Dent disease and, in some cases, absence of family history make diagnosis difficult and, thus, the disorder is likely underdiagnosed.

Differential Diagnosis

Low molecular weight (LMW) proteinuria is a prominent and characteristic feature of Dent disease and, therefore, the differential diagnosis of Dent disease includes other causes of proximal tubular dysfunction.

The presence of a more generalized proximal tubular dysfunction (glucosuria, amino aciduria, renal tubular acidosis) would suggest the possibility of a Fanconi syndrome. Causes of Fanconi syndromes can be hereditary (e.g., Wilson disease, glycogen storage disease) or acquired (e.g., exposure to heavy metal, toluene, or cisplatin).

Some individuals with Dent disease 1 with more severe proteinuria were found to have FSGS or global sclerosis on kidney biopsy [Copelovitch et al 2007, Frishberg et al 2009]. Therefore, Dent disease needs to be considered in persons with FSGS or asymptomatic proteinuria, since immunosuppressive therapies would not be effective and are potentially harmful in these individuals [Valina et al 2012].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Dent disease, the following evaluations are recommended:

  • Assessment of renal function (measured or estimated GFR; urine protein excretion)
  • Assessment for nephrocalcinosis and kidney stones by imaging studies
    • For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion)
  • Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase). Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [Wrong et al 1994].
    • For those with evidence of bone disease and/or growth delay: more complete assessment of bone health (i.e., serum vitamin D concentration and parathyroid hormone [PTH] level; x-rays of long bones for evidence of osteomalacia).
  • In children, evaluation of stature using standard growth charts

Treatment of Manifestations

No guidelines have been established for treatment of Dent disease. The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD).

Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease [Raja et al 2002, Blanchard et al 2008]. However, frequent side effects included hypokalemia, volume depletion, and cramping. Careful dosing and close monitoring for these side effects are necessary.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with proteinuria to prevent or delay further loss of kidney function; however, their effectiveness has not been clear. Note: Treatment with ACE inhibitors or ARB may be somewhat beneficial, at least in those with focal segmental glomerulosclerosis (FSGS) on kidney biopsy, as angiotensin blockade is not thought to significantly affect LMW proteinuria.

Although a high citrate diet has been shown to slow progression of CKD in clcn5 knockout mice [Cebotaru et al 2005] and has been used in the treatment of Dent disease, no human trials have proven its effectiveness. Note: Citrate is commonly used in Lowe syndrome to treat the metabolic acidosis resulting from renal tubular acidosis.

If males with Dent disease progress to ESRD, renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Since Dent disease manifestations are largely localized in the kidney, the disease will not recur.

Prevention of Secondary Complications

Bone disease has not been a prominent component of Dent disease in recent case series. When present it has been reported to respond to vitamin D supplementation and phosphorus repletion in those with elevated serum alkaline phosphatase levels [Wrong et al 1994].

Limited reports suggest that growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [Sheffer-Babila et al 2008].

Surveillance

Renal function measured as glomerular filtration rate (GFR) should be monitored at least annually together with the parameters used to stage chronic kidney disease (i.e., blood pressure, hematocrit/hemoglobin, urinary calcium excretion, and serum calcium and phosphorus concentrations).

More frequent visits and monitoring for complications of chronic kidney disease (i.e., hypertension, anemia, and secondary hyperparathyroidism) as well as consideration of intensified treatment of cardiovascular risk factors may be indicated if GFR falls below 45 mL/min/1.73m2 (CKD Stage 3B).

Agents/Circumstances to Avoid

Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided, especially if renal function is below 45 mL/min/1.73m2 (CKD stage 3B).

Evaluation of Relatives at Risk

The genetic status of male relatives at risk for Dent disease 1 (caused by mutation of CLCN5) or Dent disease 2 (caused by mutation of OCRL) can be evaluated by molecular genetic testing if the mutation in the family is known, otherwise measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dent disease is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be significantly affected. However, due to random X-chromosome inactivation, some female carriers may manifest clinically significant kidney disease.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males pass the disease-causing mutation to all of their daughters (who become carriers) and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

LMW proteins are often found to be elevated in female carriers; however, the sensitivity and specificity of such testing for carrier detection have not been established.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like Dent disease) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Kidney Foundation of Canada
    1599 Hurontario Street
    Suite 201
    Mississauga Ontario L5G 4S1
    Canada
    Phone: 800-387-4474 (toll-free); 905-278-3003
    Fax: 905-271-4990
    Email: kidney@kidney.on.ca
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261
    Email: info@kidney.org
  • International Registry for Hereditary Calcium Stone Diseases
    Mayo Clinic
    200 First Street SW
    Eisenberg SL-33
    Rochester MN 55905
    Phone: 800-270-4637 (toll-free)
    Fax: 507-255-0770
    Email: hyperoxaluriacenter@mayo.edu; rarekidneystones@mayo.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Dent Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Dent Disease (View All in OMIM)

300008CHLORIDE CHANNEL 5; CLCN5
300009DENT DISEASE 1
300535OCRL GENE; OCRL
300555DENT DISEASE 2

CLCN5

Normal allelic variants. The CLCN5 reference sequence NM_000084.2 has 12 exons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene (see Table A, Gene Symbol). The genomic reference sequence is NG_007159.2.

Pathologic allelic variants. To date, more than 100 different nonsense or missense mutations, insertions or deletions, and splicing mutations in CLCN5 have been reported [Claverie-Martin et al 2010, Devuyst & Thakker 2010], meaning that the spectrum of CLCN5 mutations is highly varied and de novo mutations are frequent.

CLCN5 mutations are scattered throughout the coding sequence of the gene and generate truncated or absent clC-5 channels in approximately 70% of cases.

Most CLCN5 mutations have not yet been fully investigated functionally. Nine that were functionally investigated [Table 3, Grand et al 2011] were classed according to their functional consequences:

  • Group 1. Mutations that lead to the retention of the mutant protein in the endoplasmic reticulum
  • Group 2. Mutations that generate a functionally defective protein devoid of electric currents and failure of endosomal acidification
  • Group 3. Mutations that lead to abnormal subcellular localization of the mature protein
  • Group 4. Mutations that generate a protein normally localized at the plasma membrane but with reduced membrane currents

Table 3. CLCN5 Pathologic Allelic Variants Discussed in This GeneReview

Mutation Group Classification 1DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Group 1c.731C>Tp.Ser244LeuNM_000084​.2
NP_000075​.1
c.815A>Gp.Tyr272Cys
Group 2c.674T>Cp.Leu225Pro
c.1020C>Ap.Asn340Lys
c.1537G>Ap.Gly513Arg
Group 3c.779G>Tp.Gly260Val
c.834G>Cp.Leu278Phe
c.1637A>Gp.Lys546Glu
c.1639T>Gp.Trp547Gly

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Grand et al [2011]

Normal gene product. The clC-5 isoform NP_000075.1, encoded by transcript NM_000084.2, comprises 746 amino acids. The protein is a voltage-dependent two chloride/proton exchanger. In human kidney, it is expressed in proximal tubular cells, alpha and beta intercalated cells of the cortical collecting tubule, and in the thick ascending limb of Henle’s loop. The protein localizes in the intracellular subapical endosomes that are involved in the reabsorption of low molecular weight proteins filtered through the glomerulus, which are normally completely reabsorbed [Smith et al 2009]. The function of the protein is to modulate the chloride concentration during proton transport [Carraro-Lacroix et al 2010, Novarino et al 2010].

Abnormal gene product. The abnormal gene products can be either shorter due to the presence of truncating mutations (nonsense or frameshifts or large DNA rearrangements) or functionally abnormal when an amino acid substitution is present. Defective activity of the protein leads to abnormal protein trafficking and reabsorption. How this causes renal failure and stones is not understood.

OCRL

Normal allelic variants. The gene comprises 5152 nucleotide base pairs and 24 exons, of which 23 are coding. One small (24-bp) alternatively spliced exon, 18a, encodes an additional eight amino acids and is expressed in neurologic tissues [Nussbaum et al 1997, Nussbaum & Suchy 2001]. It has been hypothesized that brain (but not kidney) can express an exon 8-15 splice variant [Shrimpton et al 2009] [from Lowe Syndrome, Lewis et al 2012].

Pathologic allelic variants. As detailed in Genotype/Phenotype Correlations, OCRL frameshift and nonsense mutations associated with Dent disease 2 have been mapped to different exons from those causing Lowe syndrome [Hichri et al 2011]. Note that missense, splicing, and in-frame deletion mutations causative of either disease do not map exclusively to specific gene regions. Missense mutations associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain.

Normal gene product. OCRL encodes a phosphatidylinositol 4,5-biphosphate 5-phosphatase (OCRL-1), comprising 884 amino acids, which localizes in the trans-Golgi network and the lysosomes. The protein acts as a phosphatase and removes a 5’ phosphate group from the phosphatidilinositol-4,5-biphosphate, a second messenger that plays a role in the regulation of the vesicular trafficking.

Abnormal gene product. The abnormal gene products can be either shorter due to the presence of truncating mutations (nonsense or frameshifts or large DNA rearrangements) or functionally abnormal when an amino acid substitution is present.

The mechanism by which loss of OCRL-1 protein function leads to disease has not yet been elucidated. However, OCRL-1 protein was localized to early endosomes and the trans Golgi apparatus, and clathrin coated transport intermediates [Choudhury et al 2005, Ghanekar & Lowe 2005]. Depletion of OCRL-1 perturbs trafficking at the TGN/endosome interface, suggesting a role in regulating transport between these compartments.

The abnormal vesicular trafficking shared with the CLC-5 protein may explain the overlapping clinical features associated with mutations at CLCN5 and OCRL.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Blanchard A, Vargas-Poussou R, Peyrard S, Mogenet A, Baudouin V, Boudailliez B, Charbit M, Deschesnes G, Ezzhair N, Loirat C, Macher MA, Niaudet P, Azizi M. Effect of hydrochlorothiazide on urinary calcium excretion in dent disease: an uncontrolled trial. Am J Kidney Dis. 2008;52:1084–95. [PubMed: 18976849]
  2. Bökenkamp A, Böckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr. 2009;155:94–9. [PubMed: 19559295]
  3. Carraro-Lacroix LR, Lessa LM, Bezerra CN, Pessoa TD, Souza-Menezes J, Morales MM, Girardi AC, Malnic G. Role of CFTR and ClC-5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule. Cell Physiol Biochem. 2010;26:563–76. [PubMed: 21063094]
  4. Cebotaru V, Kaul S, Devuyst O, Cai H, Racusen L, Guggino WB, Guggino SE. High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Kidney Int. 2005;68:642–52. [PubMed: 16014041]
  5. Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI. Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol. 2008;23:243–9. [PubMed: 18038239]
  6. Choudhury R, Diao A, Zhang F, Eisenberg E, Saint-Pol A, Williams C, Konstantakopoulos A, Lucocq J, Johannes L, Rabouille C, Greene LE, Lowe M. Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell. 2005;16:3467–79. [PMC free article: PMC1182289] [PubMed: 15917292]
  7. Claverie-Martin F, Ramos-Trujillo E, Garcia-Nieto V. Dent's disease: clinical features and molecular basis. Pediatr Nephrol. 2010;26:693–704. [PubMed: 20936522]
  8. Copelovitch L, Nash MA, Kaplan BS. Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol. 2007;2:914–8. [PubMed: 17702731]
  9. Davey PG, Gosling P. B2-Microglobulin instability in pathological urine. Clin Chem. 1982;28:1330–3. [PubMed: 6176371]
  10. Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis. 2010;5:28. [PMC free article: PMC2964617] [PubMed: 20946626]
  11. Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E. Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol. 2009;24:2369–73. [PubMed: 19806368]
  12. Ghanekar Y, Lowe M. Signalling for secretion. Nat Cell Biol. 2005;7:851–3. [PubMed: 16136181]
  13. Grand T, L'Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T, Genete M, Laghmani K, Teulon J, Lourdel S. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat. 2011;32:476–83. [PubMed: 21305656]
  14. Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, Baujat G, Blanchard A, Nobili F, Ranchin B, Remesy M, Salomon R, Satre V, Lunardi J. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011;32:379–88. [PubMed: 21031565]
  15. Hodgin JB, Corey HE, Kaplan BS, D'Agati VD. Dent disease presenting as partial Fanconi syndrome and hypercalciuria. Kidney Int. 2008;73:1320–3. [PubMed: 18235437]
  16. Hoopes RR Jr, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ. Evidence for genetic heterogeneity in Dent's disease. Kidney Int. 2004;65:1615–20. [PubMed: 15086899]
  17. Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ. Dent disease with mutations in OCRL1. Am J Hum Genet. 2005;76:260–7. [PMC free article: PMC1196371] [PubMed: 15627218]
  18. Lewis RA, Nussbaum RL, Brewer ED. Lowe syndrome. In: GeneReviews: Medical Genetics Information Resource (online resource). Copyright University of Washington, Seattle. 1997-2013. Available online. 2012. Accessed 5-8-12.
  19. Lloyd SE, Pearce SHS, Guenther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV. Idiopathic low molecular weight proteinuria associated with hypercalciuric nephroclacinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J Clin Invest. 1997;99:967–74. [PMC free article: PMC507905] [PubMed: 9062355]
  20. Lozanovski VJ, Ristoska-Bojkovska N, Korneti P, Gucev Z, Tasic V. OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts. World J Pediatr. 2011;7:280–3. [PubMed: 21822997]
  21. Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr. 1997;131:252–7. [PubMed: 9290612]
  22. Novarino G, Weinert S, Rickheit G, Jentsch TJ. Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis. Science. 2010;328:1398–401. [PubMed: 20430975]
  23. Nussbaum RL, Orrison BM, Jänne PA, Charnas L, Chinault AC. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet. 1997;99:145–50. [PubMed: 9048911]
  24. Nussbaum RL, Suchy SF. The oculocerebrorenal syndrome of Lowe (Lowe syndrome). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. Chap 252. New York, NY: McGraw-Hill; 2001:6257-66.
  25. Raja KA, Schurman S, D'Mello R G, Blowey D, Goodyer P, Van Why S, Ploutz-Snyder RJ, Asplin J, Scheinman SJ. Responsiveness of hypercalciuria to thiazide in Dent's disease. J Am Soc Nephrol. 2002;13:2938–44. [PubMed: 12444212]
  26. Reinhart SC, Norden AG, Lapsley M, Thakker RV. et al. Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. J Am Soc Nephrol. 1995;5:1451–61. [PubMed: 7703383]
  27. Scheinman SJ, Cox JP, Lloyd SE, Pearce SH, Salenger PV, Hoopes RR, Bushinsky DA, Wrong O, Asplin JR, Langman CB, Norden AG, Thakker RV. Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int. 2000;57:232–9. [PubMed: 10620204]
  28. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 1998;53:3–17. [PubMed: 9452994]
  29. Sheffer-Babila S, Chandra M, Speiser PW. Growth hormone improves growth rate and preserves renal function in Dent disease. J Pediatr Endocrinol Metab. 2008;21:279–86. [PubMed: 18540256]
  30. Shrimpton AE, Hoopes RR, Knohl SJ, Hueber P, Reed AA, Christie PT, Igarashi T, Lee P, Lehman A, White C, Milford DV, Sanchez MR, Unwin R, Wrong OM, Thakker RV, Scheinman SJ. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol. 2009;112:27–36. [PubMed: 19390221]
  31. Smith AJ, Reed AA, Loh NY, Thakker RV, Lippiat JD. Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol. 2009;296:F390–7. [PMC free article: PMC2643861] [PubMed: 19019917]
  32. Tasic V, Lozanovski VJ, Korneti P, Ristoska-Bojkovska N, Sabolic-Avramovska V, Gucev Z, Ludwig M. Clinical and laboratory features of Macedonian children with OCRL mutations. Pediatr Nephrol. 2011;26:557–62. [PubMed: 21249396]
  33. Tosetto E, Addis M, Caridi G, Meloni C, Emma F, Vergine G, Stringini G, Papalia T, Barbano G, Ghiggeri GM, Ruggeri L, Miglietti N. D Angelo A, Melis MA, Anglani F. Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatr Nephrol. 2009;24:1967–73. [PubMed: 19582483]
  34. Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Bröking E, Laube G, Neb M, Nuutinen M, Ozaltin F, Rascher W, Ring T, Tasic V, van Wijk JA, Ludwig M. Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis. 2006; 48:942.e1-14. [PubMed: 17162149]
  35. Valina MR, Larsen CP, Kanosky S, Suchy SF, Nield LS, Onder AM. A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis. Clin Nephrol. 2012 [PubMed: 22735364]
  36. Wrong OM, Norden AG, Feest TG. Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM. 1994;87:473–93. [PubMed: 7922301]

Chapter Notes

Author Notes

Rare Kidney Stone Consortium

Rare Diseases Clinical Research Network - Rare Kidney Stone Consortium

The Rare Kidney Stone Consortium is a resource for patients, their families, and physicians. The center facilitates collaborative research to provide better understanding of Dent Disease and other rare types of kidney stones. For more information about Dent disease, please e-mail the Rare Kidney Stone Consortium at rarekidneystones@mayo.edu or call 800-270-4637.

Revision History

  • 9 August 2012 (me) Review posted live
  • 1 March 2012 (jcl) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK99494PMID: 22876375
PubReader format: click here to try

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...