CLDN16 – Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; Renal Hypomagnesemia 3) is an ultra-rare autosomal recessive tubulopathy caused by biallelic variants in CLDN16, encoding the tight junction protein paracellin-1. Affected individuals present in early childhood with renal magnesium wasting, hypercalciuria and bilateral nephrocalcinosis, often progressing to chronic kidney disease and end-stage renal failure.

Patients typically exhibit hematuria, polyuria, polydipsia, nephrocalcinosis and hypomagnesemia, with hypercalciuria often unresponsive to thiazide diuretics (PMID:14586675). Onset can range from infancy to adolescence, with variable rates of progression to renal insufficiency.

Inheritance is autosomal recessive with robust segregation across multiple sibships, including consanguineous families with up to seven affected siblings (PMID:24321194). Over 100 probands from >20 unrelated families have been reported, with compound heterozygous and homozygous variants confirming the gene–disease relationship.

The variant spectrum includes >50 missense variants, at least 15 loss-of-function alleles (nonsense, splice-site), and several large multi-exon deletions. A recurrent founder allele, c.453G>T (p.Leu151Phe), accounts for a high proportion of cases in certain populations (PMID:15856319).

Mechanistically, pathogenic CLDN16 variants cause mislocalization of paracellin-1 from tight junctions to endoplasmic reticulum or lysosomes, leading to impaired paracellular Mg2+ and Ca2+ reabsorption. Functional assays in MDCK cells demonstrate intracellular retention and reduced Mg2+ flux (PMID:16528408), while inhibition of clathrin-mediated endocytosis can rescue surface expression of certain truncating mutants (PMID:16501001). A murine model lacking Cldn16 recapitulates both renal and enamel defects, confirming the role of CLDN16 in tubular and ameloblast tight junctions (PMID:26426912).

Heterozygous carriers may occasionally display mild hypercalciuria or stone formation without full FHHNC phenotype, indicating dose-dependent effects and allele-specific expressivity (PMID:14628289).

In summary, biallelic CLDN16 variants cause definitive FHHNC via loss-of-function and tight junction mistrafficking, with clear genotype–phenotype correlations and therapeutic implications. Genetic testing for CLDN16 is essential for early diagnosis, family counseling, and potential targeted rescue strategies. Key take-home: Comprehensive CLDN16 analysis informs prognostication and guides precise management of FHHNC.

References

• Pediatric nephrology (Berlin, Germany) • 2003 • Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC. PMID:14586675
• American journal of human genetics • 2003 • A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting. PMID:14628289
• Pediatric nephrology (Berlin, Germany) • 2005 • Hypomagnesemia with hypercalciuria and nephrocalcinosis: case report and a family study. PMID:15856319
• BMC research notes • 2013 • A novel CLDN16 mutation in a large family with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. PMID:24321194
• Nephrology, dialysis, transplantation • 2015 • Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations. PMID:25477417
• The Journal of clinical investigation • 2006 • Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16. PMID:16528408
• Human molecular genetics • 2006 • Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail. PMID:16501001
• Journal of bone and mineral research • 2016 • Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation. PMID:26426912

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