Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Chloride channel 5

The gene codes a chloride channel. Mutations cause Dent disease.

Epidemiology

The frequency of CLCN5 mutations in general population is not known. We find mutations in this gene throughout the world. In Japan 70% of children with low molecular weight proteinuria carry mutation of this gene.

Gene Structure

The gene CLCN5 responsible for Dent disease type 1 is the voltage-gated chloride channel (CLCK2 or CLC5). The gene is located on the X chromosome and therefore is inherited depending on sex. The exact locus is (Xp11.22.) The gene with a size of about 25 kb consists of 12 exons, 11 are translated.

Expression

The gene is expressed in renal proximal tubule cells. Expression is highest below the brush border in a region densely packed with endocytotic vesicles. Colocalization with the H(+)-ATPase and with internalized proteins suggests its function in reabsorbtion of filtered proteins. In intercalated cells of the collecting duct it again localizes to apical intracellular vesicles and colocalizes with the proton.

Phenotype

Typical are various renal tubular disorders which result in kidney stone formation (nephrolithiasis), hypophosphatemic rickets, low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. Sometimes additionally hematuria, glycosuria, aminoaciduria, impaired urinary concentrating ability, and mild decrease in creatinine clearance can be seen.

Test Strategy

Unclear cases of proteinuria, hypercalciuria, and hypophosphatemia. Family counseling in case of familiar hypophosphatemic rickets.

Interpretation

The clinical importance is in clarifying the reason of proteinuria. Maybe preventing a child from renal biopsy.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Urolithiasis
Cystinuria
SLC3A1
SLC7A9
Dicarboxylic aminoaciduria
SLC1A1
Dihydroxyadenin urolithiasis
APRT
Nephrocalcinosis
Bartter syndrome
Antenatal Bartter syndrome type 1
SLC12A1
Antenatal Bartter syndrome type 2
KCNJ1
Classic Bartter syndrome
CLCNKB
Hypercalciuric hypocalcemia 1
CASR
Hypercalciuric hypocalcemia 2
GNA11
Infantile Bartter syndrome with deafness type 4
BSND
CLCNKA
CLCNKB
Transient antenatal Bartter syndrome
MAGED2
Dent disease
CLCN5
OCRL
Hereditary Rickets
Hypophosphatasia
Adult hypophosphatasia
ALPL
Childhood hypophosphatasia
ALPL
Infantile hypophosphatasia
ALPL
Odontohypophosphatasia
ALPL
Hypophosphatemic bone and kindney disease
Disorders of the renal phosphate transporters
Hypophosphatemic rickets with hypercalciuria
SLC34A3
Idiopathic basal ganglia calcification 1
SLC20A2
Nephrolithiasis/osteoporosis, hypophosphatemic, 1
SLC34A1
Nephrolithiasis/osteoporosis, hypophosphatemic, 2
SLC9A3R1
FGF23-induced hypophosphatemic rickets
Autosomal dominant hypophosphatemic rickets
FGF23
Autosomal recessive hypophosphatemic rickets type 1
DMP1
Autosomal recessive hypophosphatemic rickets type 2
ENPP1
X-linked dominant hypophosphatemic rickets
PHEX
Fanconi-type hypophosphatemic rickets
Nephrolithiasis/osteoporosis, hypophosphatemic, 1
SLC34A1
X-linked recessive hypophosphatemic rickets
CLCN5
OCRL
Hypophosphatemic rickets with hyperparathyroidism
KL
Osteoglophonic dysplasia
FGFR1
Raine syndrome
FAM20C
X-linked dominant hypophosphatemic rickets
PHEX
Vitamin D hydroxylation-deficient rickets type 1A
CYP27B1
Vitamin D hydroxylation-deficient rickets type 1B
CYP2R1
Vitamin D-dependent rickets, type 2A
VDR
Vitamin D-dependent rickets, type 2B
RXRA
Hyperoxaluria
Hyperoxaluria type 1
AGXT
Hyperoxaluria type 2
GRHPR
Hyperoxaluria type 3
HOGA1
Hypomagnesemia with hypercalciuria and nephrocalcinosis
CLDN16
Hypomagnesemia with hypercalciuria and nephrocalcinosis with ocular involvement
CLDN19
Infantile hypercalcemia
CYP24A1
Lowe disease
OCRL
Renal tubular acidosis
Combined renal tubular acidosis 3 with osteopetrosis 3
CA2
Distal renal tubular acidosis (autosomal dominant)
SLC4A1
Distal renal tubular acidosis (autosomal recessive)
ATP6V0A4
Distal renal tubular acidosis with deafness (autosomal recessive)
ATP6V1B1
Proximal renal tubular acidosis
SLC4A4
Renal tubular acidosis with arthrogryposis
Arthrogryposis, renal dysfunction, and cholestasis 1
VPS33B
Arthrogryposis, renal dysfunction, and cholestasis 2
VIPAS39
Williams-Beuren syndrome
ELN
Nephrolithiasis diarrhea syndrome
SLC26A6
Susceptibility to nephrolithiasis
ALPL
CASR
SLC26A1
TRPV5
ZNF365
Uric acid nephropathy
Hyperuricemic nephropathy
Hyperuricemic nephropathy, familial juvenile 1
UMOD
Hyperuricemic nephropathy, familial juvenile 2
REN
Kelley-Seegmiller syndrome
HPRT1
Lesch-Nyhan syndrome
HPRT1
Renal Hypouricemia
SLC22A12
SLC2A9
Dent disease
CLCN5
OCRL
X-linked recessive hypophosphatemic rickets
CLCN5
OCRL

References:

1.

Langman CB et al. (2004) The molecular basis of kidney stones.

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2.

Thakker RV et al. (2000) Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis.

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Update: Sept. 26, 2018