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Dent Disease

, MD, , MD, , MD, , PhD, , PhD, , BS, and .

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

Initial Posting: ; Last Update: September 25, 2014.


Clinical 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 mutation of 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.


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


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 either by molecular genetic testing (if the pathogenic variant in the family is known) or by 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 pathogenic variant. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. Affected males pass the pathogenic variant 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 pathogenic variant in the family has been identified.


Suggestive Findings

Diagnosis of Dent disease should be suspected in individuals with the three criteria below in the absence of other known causes of proximal tubule dysfunction [Hoopes et al 2004, Edvardsson et al 2013]. Note: A possible diagnosis of Dent disease is considered if LMW proteinuria and at least one other criterion are present.


LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) 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] and thus could theoretically yield a false negative result.



  • 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.

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 pathogenic variant 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

In random urine collections

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].

Establishing the Diagnosis

The diagnosis of Dent disease is established in a proband with the identification of a pathogenic variant in either CLCN5 or OCRL (see Table 2).

One genetic testing strategy is molecular genetic testing of CLCN5 (Dent disease 1) or OCRL (Dent disease 2).

An alternative genetic testing strategy is use of a multi-gene panel that includes CLCN5, OCRL, and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 2.

Summary of Molecular Genetic Testing Used in Dent Disease

Gene 1
Proportion of Dent Disease Attributed to Mutation of This Gene 2Test Method
(Dent disease1)
60%Sequence analysis 3, 4, 5, 6
Deletion/duplication analysis 6, 7
(Dent disease 2)
15%Sequence analysis 3, 4, 5, 8
Deletion/duplication analysis 7, 8
Unknown 9NA

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.


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


Of the 174 different CLCN5 pathogenic variants known to cause Dent disease 1 identified to date, ~5% are gross rearrangements (large deletions, insertions, or indels).


Testing that identifies exonic or whole-gene deletions/duplications not 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.


Of the 40 different OCRL pathogenic variants known to cause Dent disease 2 identified to date, 5% are multiexon deletions.


Approximately 25% of those with Dent disease do not have an identified pathogenic variant in CLCN5 or OCRL, suggesting additional genetic heterogeneity [Hoopes et al 2004, Hoopes et al 2005].

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at EuroGentest [Ludwig et al 2014 (full text)].

Clinical Characteristics

Clinical Description

In the early stages of Dent disease, children (typically <~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]. Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption.

An estimated 30%-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 pathogenic variant manifests only asymptomatic hypercalciuria and/or proteinuria without developing CKD.

Some individuals with a pathogenic variant 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, and 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 pathogenic variants in about 15% of individuals with Dent disease, it has been suggested that pathogenic variants 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.

An estimated 6/11 males with an OCRL pathogenic variant 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 pathogenic variants 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 one family reported, 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 pathogenic variant 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 pathogenic variant; 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 pathogenic variant. Urine B2 microglobulin excretion was increased in males with an OCRL pathogenic variant (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 a CLCN5 or an OCRL pathogenic variant [Cho et al 2008].

Symptomatic Females

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 CLCN5 or OCRL pathogenic variant on the remaining X chromosome).

Although not reported in the literature, a female with biallelic pathogenic variants 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 mutation of OCRL is 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 Characteristics).

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, OCRL missense and splicing mutations and in-frame deletions 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].


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; 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 2013].

Donnai-Barrow syndrome, caused by mutation of LRP2 which encodes megalin, a 600-kd multiligand endocytic receptor, bears some similarities to Dent disease [Kantarci et al 2007]. Clinical manifestations of this rare disorder include hypertelorism, large anterior fontanelle, agenesis of the corpus callosum and congenital diaphragmatic hernia [Pober et al 2009]. Low molecular-weight proteinuria and high myopia, have been consistently observed in these patients [Pober et al 2009]. However, other typical findings of Dent disease, including nephrolithiasis, nephrocalcinosis, hypercalciuria, chronic kidney disease, or bone disease have not been reported to date.


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
  • Medical genetics consultation

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. Because 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].


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/1.73 m2 (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/1.73 m2 (CKD stage 3B).

Evaluation of Relatives at Risk

It is appropriate to evaluate male relatives at risk for Dent disease 1 (caused by mutation of CLCN5) or Dent disease 2 (caused by mutation of OCRL) in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, 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 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

  • The father of an affected male will not have the disease nor will he be a carrier of a CLCN5 or OCRL pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo mutation and, thus, the mother is not a carrier. The frequency of de novo mutations is not known.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a CLCN5 or OCRL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed 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 pathogenic variant 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 pathogenic variant 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 CLCN5 or OCRL pathogenic variant 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the CLCN5 or OCRL pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Dent disease) 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 CLCN5 or OCRL pathogenic variant has been identified.


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)
    United Kingdom
    Phone: 0800-652-3181
  • Kidney Foundation of Canada
    310-5160 Decarie Blvd.
    Montreal Ontario H3X 2H9
    Phone: 800-361-7494 (toll-free); 514-369-4806
    Fax: 514-369-2472
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
  • Rare Kidney Stone Consortium Registry
    Phone: 800-270-4637 (toll-free)

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)



Gene structure. 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.

Pathogenic allelic variants. To date 174 different CLCN5 pathogenic variants known to cause Dent disease type 1. The majority of these are private: ~74% of all mutations have been found in only one family, common mutations, found in ≥4 families, are summarized in Table 4 (pdf). Approximately 52% are truncating, ~42% non-truncating, and ~5% gross rearrangements (large deletions, insertions or indels).

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

Most CLCN5 pathogenic variants 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. Pathogenic variants that lead to the retention of the mutant protein in the endoplasmic reticulum
  • Group 2. Pathogenic variants that generate a functionally defective protein devoid of electric currents and failure of endosomal acidification
  • Group 3. Pathogenic variants that lead to abnormal subcellular localization of the mature protein
  • Group 4. Pathogenic variants that generate a protein normally localized at the plasma membrane but with reduced membrane currents

Table 3.

CLCN5 Pathogenic Allelic Variants Discussed in This GeneReview

Variant Group Classification 1DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Group 1c.731C>Tp.Ser244LeuNM_000084​.2
Group 2c.674T>Cp.Leu225Pro
Group 3c.779G>Tp.Gly260Val

Note on variant classification: Variants listed in the table have been provided by the authors. 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​ See Quick Reference for an explanation of nomenclature.

For detailed information on CLCN5 and OCRL pathogenic variants, see Tables 4 and 5 (pdf).

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.


Gene structure. The gene comprises 5152 nucleotide base pairs and 24 exons, of which 23 are coding. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. 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, Lowe Syndrome].

Pathogenic allelic variants. Forty different pathogenic variants are known to cause Dent disease type 2; however, this number may be over- or underestimated due to the phenotypic overlap of Dent disease type 2 with Lowe syndrome. The majority (~85%) of pathogenic variants are private; common mutations (i.e., those found in ≥4 families) are summarized in Table 4 (pdf).

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. One deletion of exons 3 and 4 was reported in an affected male [Hichri et al 2011]. Of the known OCRL Dent disease 2-causing mutations, 47.5% are truncating, 47.5% non-truncating, and 5% multiexon deletions

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 mutation of CLCN5 and OCRL.


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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 or call 800-270-4637.

Author History

Lada Beara-Lasic, MD (2012-present)
Andrea Cogal, BS (2014-present)
Peter Harris, PhD (2014-present)
Katharina Hopp, PhD (2014-present)
John C Lieske, MD (2012-present)
Kari Mattison (2014-present)
Dawn S Milliner, MD (2012-present)
Sandro Rossetti, MD; Mayo Clinic (2012-2014)

Revision History

  • 25 September 2014 (me) Comprehensive update posted live
  • 9 August 2012 (me) Review posted live
  • 1 March 2012 (jcl) Original submission
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