Correction: Claudin-19 Mutations and Clinical Phenotype in Spanish Patients with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsortion in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

Claudins in Renal Physiology and Pathology

“…FHHNC is characterized by an excessive urinary loss of Ca 2+ and Mg 2+ , resulting in hypomagnesemia and hypercalciuria. Patients have nephrocalcinosis (a parenchymal deposition of calcium-based crystal in the renal parenchyma) and renal failure that may progress toward end stage renal disease early in life [26,45,[49][50][51]. Of note, hypomagnesemia can be absent [51,52].…”

“…Age at onset ranges from 0 to more to 30 years for CLDN16 [45,49,50,[52][53][54][55][56] and CLDN19 mutations [50,51,57,58] and the diagnosis can be delayed.…”

“…Patients with CLDN19 mutations frequently display severe ocular abnormalities (myopia, pigmentary retinitis, macular coloboma, strabismus, astigmatism, nystagmus, macular scars, macular degeneration, anisocoria, retinochoroiditis) [50,51,57,58,68], contrasting with milder and rarer ocular abnormalities reported with CLDN16 mutations (strabismus, myopia, astigmatism, hypermetropia) [45]. CLDN19 is expressed in human fetal retinal pigment epithelium; claudin 19 may be involved in the development and the function of retinal pigment epithelium and retinal neurogenesis [69,70].…”

“…Bone disease [74], bone deformities [62], failure to thrive [50][51][52]62,75] and rickets [45,52,62,76] are reported but their exact pathophysiological mechanisms need to be elucidated.…”

“…The effectiveness of these treatments on the course of nephrocalcinosis and on the decline of GFR in FHHNC is unknown. Hydrochlorothiazide has been shown to be effective in correcting hypercalciuria due to CLDN16 mutations in some [52,79] but not all patients [50][51][52]. Mg 2+ supplementation might also be ineffective to correct hypomagnesemia [50][51][52].…”