Scientific background:

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

Gene: 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.

Molecular anatomy: 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.

Clinical signs: 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.

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.

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

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

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Langman CB et al. (2004) The molecular basis of kidney stones.
Thakker RV et al. (2000) Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis.