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.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: variable phenotypic expression in three affected sisters from Mexican ancestry

“…Although the disease is usually a pediatric diagnosis, in the three sisters herein reported, etiologic diagnosis was delayed until their fourth decade of life. Interestingly the mutation identified in this family, a glycine to asparagine substitution, at position 20 (p.Gly20Asp) of the protein, 2,8,9 has been almost exclusively reported in families from Spain and Southwest France origin, where a founder effect was established. 9 To our knowledge, this is the first report of a Mexican family with FHHNC and although for the p.Gly20Asp mutation endogamy and a founder effect has been described for the disease parental consanguinity was denied in the family reported herein.…”

“…CLDN19 is expressed with highest levels in the kidney and the eye 2,9 being both, renal and ocular manifestations in the affected sisters in agreement with previous reports. 2,8,9 The above-mentioned endorse the described phenotypic variability, 10 making difficult to define a clear genotype-phenotype correlation. 3 Interestingly, the heterozygous mother, although did not exhibited clinical and ultrasound manifestations of renal disease, showed a significant hypercalciuria even higher than their three affected daughters and normal but low reference values of serum magnesium, thus being discarded as a possible donor.…”

“…3 A growing number of different mutations in both genes 2,4-10 were identified in patients with FHHNC, with variable phenotypic expression among patients with the same mutation, but with a private characteristic of CLDN19 gene mutations that differentiate them from CLDN16 mutations, the important and variable visual involvement. 9 Mutations in CLDN16 and CLDN19 occur throughout the coding region and can affect proper folding, intracellular trafficking of the protein, or its paracellular pore forming function. [11][12][13] Herein, we present the first case report of a Mexican family with three affected sisters carrying a p.Gly20Asp mutation in CLDN19.…”

Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement

“…A founder effect has been shown for the recurrent disease-causing variant c.59G4A (p.G20D) in Spanish and French families. 2,10,17 The GeneBank accession numbers for CLDN16 and CLDN19 are NG_008149.1, NM_006580.3 and NG_008993.1, NM_148960.2, respectively. Reference CLDN16 (ENSG00000113946) and CLDN19 (ENSG00000164007) sequences can also be found in the Ensembl database (http://www.ensembl.org).…”

“…However, these treatments do not seem to have a considerable effect on the levels of urinary calcium or serum magnesium. 10,17 Severe myopia can be corrected with glasses, contact lenses, laser surgery or implanting artificial lenses. There is currently no cure for nystagmus or for coloboma.…”