title: 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 reabsorption 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.
authors.affiliation: Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. fclamar@gobiernodecanarias.org
authors.forename: Félix
authors.initials: F
authors.lastname: Claverie-Martín
authors.forename: Víctor
authors.initials: V
authors.lastname: García-Nieto
authors.forename: Cesar
authors.initials: C
authors.lastname: Loris
authors.forename: Gema
authors.initials: G
authors.lastname: Ariceta
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Nadal
authors.forename: Laura
authors.initials: L
authors.lastname: Espinosa
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Fernández-Maseda
authors.forename: Montserrat
authors.initials: M
authors.lastname: Antón-Gamero
authors.forename: Africa
authors.initials: A
authors.lastname: Avila
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Madrid
authors.forename: Hilaria
authors.initials: H
authors.lastname: González-Acosta
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Córdoba-Lanus
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.forename: Marta
authors.initials: M
authors.lastname: Gil-Calvo
authors.forename: Mar
authors.initials: M
authors.lastname: Espino
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martinez
authors.forename: Ana
authors.initials: A
authors.lastname: Sanchez
authors.forename: Rafael
authors.initials: R
authors.lastname: Muley
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D057167:Claudins / Q000235:genetics*; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053565:Hypercalciuria / Q000150:complications / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008275:Magnesium Deficiency / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009397:Nephrocalcinosis / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D013030:Spain; D055815:Young Adult
chemical_list: C508912:CLDN19 protein, human; D057167:Claudins