Publication: Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.
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Identifiers
Date
2013
Authors
Claverie-Martín, Félix
García-Nieto, Víctor
Loris, César
Ariceta, Gema
Nadal, Inmaculada
Espinosa, Laura
Fernández-Maseda, Ángeles
Antón-Gamero, Montserrat
Ávila, África
Madrid, Álvaro
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
PLOS ONE Editorial Board
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.
Description
Journal Article; Research Support, Non-U.S. Gov't;
MeSH Terms
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young Adult
Medical Subject Headings::Named Groups::Persons::Age Groups::Child::Child, Preschool
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Claudins
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis
Medical Subject Headings::Check Tags::Female
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Urological Manifestations::Hypercalciuria
Medical Subject Headings::Diseases::Female Urogenital Diseases and Pregnancy Complications::Female Urogenital Diseases::Urologic Diseases::Kidney Diseases::Kidney Diseases, Cystic::Polycystic Kidney Diseases
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Malnutrition::Deficiency Diseases::Magnesium Deficiency
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle Aged
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Biological::Models, Genetic
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Calcium Metabolism Disorders::Calcinosis::Nephrocalcinosis
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype::Endophenotypes
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic
Medical Subject Headings::Geographicals::Geographic Locations::Europe::Spain
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young Adult
Medical Subject Headings::Named Groups::Persons::Age Groups::Adolescent
Medical Subject Headings::Named Groups::Persons::Age Groups::Child::Child, Preschool
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Claudins
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis
Medical Subject Headings::Check Tags::Female
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Urological Manifestations::Hypercalciuria
Medical Subject Headings::Diseases::Female Urogenital Diseases and Pregnancy Complications::Female Urogenital Diseases::Urologic Diseases::Kidney Diseases::Kidney Diseases, Cystic::Polycystic Kidney Diseases
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Malnutrition::Deficiency Diseases::Magnesium Deficiency
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle Aged
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Biological::Models, Genetic
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Calcium Metabolism Disorders::Calcinosis::Nephrocalcinosis
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype::Endophenotypes
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic
Medical Subject Headings::Geographicals::Geographic Locations::Europe::Spain
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young Adult
Medical Subject Headings::Named Groups::Persons::Age Groups::Adolescent
DeCS Terms
CIE Terms
Keywords
Kidneys, Magnesium, Mutation detection, Polymerase chain reaction, Renal transplantation, Substitution mutation, Riñones, Magnesio, Detección de mutaciones, Reacción en cadena de la polimerasa, Transplante renal, Mutación de sustitución
Citation
Claverie-Martín F, García-Nieto V, Loris C, Ariceta G, Nadal I, Espinosa L, et al. Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. PLoS ONE. 2013;8(1):e53151