CLDN19 – Renal Hypomagnesemia 5 with Ocular Involvement

CLDN19 is linked to autosomal recessive renal hypomagnesemia 5 with ocular involvement, a disorder characterized by renal magnesium wasting, hypercalciuria, nephrocalcinosis, progressive chronic kidney disease, and variable bilateral chorioretinal atrophy. Patients typically present in childhood with hypomagnesemia and elevated urinary calcium, leading to nephrolithiasis and renal insufficiency. Ocular manifestations range from pigmentary retinopathy to severe chorioretinal degeneration, reflecting the high expression of claudin-19 in the kidney and retina.

Genetic evidence includes four unrelated probands in four pedigrees with biallelic missense variants in CLDN19 (PMID:17033971; PMID:21791920; PMID:30576809; PMID:34504727). Segregation in a consanguineous Pakistani family demonstrated three affected relatives homozygous for c.389G>A (p.Gly130Asp) (PMID:21791920). Variants are predominantly missense substitutions clustering in the first extracellular loop and second transmembrane domain, with recurrent alleles observed in European and Middle Eastern populations.

The variant spectrum comprises primarily missense changes (e.g., c.389G>A (p.Gly130Asp)), with rare splice-altering and deep-intronic alleles reported. No large deletions or truncating variants have been described in affected individuals. Compound heterozygosity and homozygosity for deleterious variants underlie the clinical phenotype, with a consistent autosomal recessive inheritance pattern.

Functional studies reveal that pathogenic CLDN19 variants abrogate tight-junction assembly and basolateral membrane trafficking in renal tubular epithelial cells, leading to paracellular cation leak and magnesium loss (PMID:17033971). In vitro assays in MDCK cells show disrupted claudin-19 localization, while minigene analyses confirm splicing defects for select alleles. The mechanism is consistent with loss of paracellular barrier function rather than dominant negative effects.

Ocular pathology is recapitulated in murine models and human induced pluripotent stem cell–derived retinal pigment epithelium. Mutant claudin-19 expression in mouse retina diminishes P1 electroretinogram amplitude, increases outer nuclear layer apoptosis, and impairs bipolar cell morphology; these defects are partially rescued by 9-cis-retinal supplementation (PMID:30937396). Concordant cellular and animal data support pathogenicity and clarify the dual renal-retinal impact of CLDN19 deficiency.

Integration of genetic and functional data yields a Strong gene–disease association, meeting ClinGen criteria with multiple unrelated probands, segregation, and concordant experimental evidence. Genetic evidence is Strong (“four unrelated probands; segregation with three affected relatives”) and functional evidence is Moderate (“cellular and murine models demonstrate tight-junction disruption and partial rescue”). Additional studies on transcriptional regulation and promoter analysis exist but exceed scoring parameters. Key take-home: Biallelic CLDN19 variants cause a clinically distinctive autosomal recessive tubulopathy with ocular involvement, guiding molecular diagnosis and personalized management.

References

• American Journal of Human Genetics • 2006 • Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. PMID:17033971
• American Journal of Nephrology • 2011 • Mutation in the tight-junction gene claudin 19 (CLDN19) and familial hypomagnesemia, hypercalciuria, nephrocalcinosis (FHHNC) and severe ocular disease. PMID:21791920
• Gene • 2019 • Characterization of two novel mutations in the claudin-16 and claudin-19 genes that cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis. PMID:30576809
• Journal of Pediatric Genetics • 2021 • Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19. PMID:34504727
• Communications Biology • 2019 • Disease-associated mutations of claudin-19 disrupt retinal neurogenesis and visual function. PMID:30937396

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