CLDN19 – Renal Hypomagnesemia 3

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; renal hypomagnesemia 3) is an autosomal recessive renal tubular disorder caused by biallelic pathogenic variants in CLDN19. The disease typically presents in childhood with hypomagnesemia, hypercalciuria, nephrocalcinosis, polyuria, polydipsia, recurrent urinary tract infections, and progressive chronic kidney disease often culminating in end‐stage renal failure. Patients with CLDN19 mutations additionally exhibit severe ocular involvement including high myopia, nystagmus, rod–cone dystrophy, and macular/scar lesions.

Genetic evidence comprises 23 genetically confirmed patients from 26 unrelated families harboring biallelic CLDN19 variants, with segregation in multiple consanguineous and non‐consanguineous pedigrees and a recurrent founder missense allele p.Gly20Asp ([PMID:22422540]). A Spanish founder effect for c.59G>A (p.Gly20Asp) has been demonstrated by haplotype analysis in 27 patients ([PMID:25410674]). Case reports describe additional compound heterozygous and homozygous variants, including nonsense c.507G>A (p.Trp169Ter), frameshift c.140_141del (p.Tyr47_Ile77del), missense c.389G>A (p.Gly130Asp), and splice-site c.474-1G>A.

Functional studies confirm high CLDN19 expression in the thick ascending limb of Henle’s loop and retina. Disease‐associated mutations impair tight junction assembly, paracellular Mg2+ and Ca2+ permeability, and protein trafficking in cellular assays ([PMID:17033971]). In vivo models and retinal organoid experiments demonstrate disrupted retinal pigment epithelium differentiation and impaired electroretinogram responses that can be partially rescued by 9-cis-retinal ([PMID:30937396]).

No published reports dispute the CLDN19–renal hypomagnesemia 3 association. The concordance of genetic, segregation, and functional data supports a Strong clinical validity classification.

Key Take-home: Biallelic CLDN19 variants cause autosomal recessive renal hypomagnesemia 3 with characteristic renal and ocular phenotypes; targeted genetic testing and early recognition enable informed clinical management and family counseling.

References

• Clinical Journal of the American Society of Nephrology • 2012 • Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations PMID:22422540
• World Journal of Pediatrics • 2015 • Haplotype analysis of CLDN19 single nucleotide polymorphisms in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis PMID:25410674
• 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
• Communications Biology • 2019 • Disease-associated mutations of claudin-19 disrupt retinal neurogenesis and visual function PMID:30937396

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