title: The role of tight junctions in paracellular ion transport in the renal tubule: lessons learned from a rare inherited tubular disorder.
abstract: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive renal tubular disorder that typically presents with disturbances in magnesium and calcium homeostasis, recurrent urinary tract infections, and polyuria and/or polydipsia. Patients with FHHNC have high risk of the development of chronic kidney disease and end-stage renal disease in early adolescence. Multiple distinct mutations in the CLDN16 gene, which encodes a tight junction protein, have been found responsible for this disorder. In addition, mutations in another member of the claudin family, CLDN19, were identified in a subset of patients with FHHNC with visual impairment. The claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo- and epithelial cells. Claudins are especially important for the regulation of paracellular ion permeability. We describe a Brazilian family with 2 affected siblings presenting with the typical FHHNC phenotype with ocular anomalies. The clinical diagnosis of FHHNC was confirmed using mutational analysis of the CLDN19 gene, which showed 2 compound heterozygous mutations. In the context of the case vignette, we summarize the clinical presentation, diagnostic criteria, and therapeutic options for patients with FHHNC. We also review recent advances in understanding the electrophysiologic function of claudin-16 and -19 in the thick ascending limb of the loop of Henle and implications for ion homeostasis in the human body.
authors.affiliation: Department of General Pediatrics, University Children's Hospital Muenster, Münster, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Haisch
authors.forename: Jorge Reis
authors.initials: JR
authors.lastname: Almeida
authors.forename: Paulo Roberto
authors.initials: PR
authors.lastname: Abreu da Silva
authors.forename: Karl Peter
authors.initials: KP
authors.lastname: Schlingmann
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
mesh_terms: D000293:Adolescent; D002118:Calcium / Q000378:metabolism; D057167:Claudins; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics / Q000503:physiopathology; D017136:Ion Transport / Q000502:physiology; D007684:Kidney Tubules / Q000503:physiopathology*; D008274:Magnesium / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D009397:Nephrocalcinosis / Q000235:genetics / Q000503:physiopathology; D015499:Renal Tubular Transport, Inborn Errors / Q000235:genetics / Q000503:physiopathology; D019108:Tight Junctions / Q000502:physiology*; D055815:Young Adult
chemical_list: C508912:CLDN19 protein, human; D057167:Claudins; D008565:Membrane Proteins; C502010:claudin 16; D008274:Magnesium; D002118:Calcium