Affinage

CLDN16

Claudin-16 · UniProt Q9Y5I7

Length
235 aa
Mass
26.1 kDa
Annotated
2026-06-09
34 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLDN16 (paracellin-1) is a renal tight junction protein expressed predominantly in the thick ascending limb of the loop of Henle, where it forms the paracellular pathway for reabsorption of the divalent cations Ca2+ and Mg2+ (PMID:10878661, PMID:20147368). Targeted deletion of murine Cldn16 produces hypercalciuria and hypomagnesemia, and the loss of paracellular transport triggers compensatory upregulation of transcellular Ca2+/Mg2+ transport genes including Trpv5, Trpm6, calbindin-D9k, Cnnm2, and Atp13a4 (PMID:20147368). The bridging function depends on both extracellular loops: mutations in the first and second extracellular loops abolish paracellular conductance (PMID:10878661, PMID:18816383), and the degree of residual claudin-16 activity scales inversely with disease severity, establishing a dose-dependent relationship between protein function and renal divalent-cation handling (PMID:18003771). Loss-of-function mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) (PMID:18003771), and a substantial fraction of exonic mutations act not by amino-acid substitution but by disrupting pre-mRNA splicing through inactivation of exonic splicing enhancers, cryptic splice-site activation, and exon skipping (PMID:30621608). Beyond its renal role, the mechanistic basis of CLDN16 function in non-renal tissues has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 Medium

    Established the gene's identity and core role: linking CLDN16 to renal paracellular divalent-cation reabsorption and identifying the extracellular loop as the functional determinant of intercellular bridging.

    Evidence Linkage analysis and mutation-to-domain mapping in FHHNC families

    PMID:10878661

    Open questions at the time
    • No in vitro reconstitution of channel activity
    • Selectivity mechanism for Ca2+ vs Mg2+ not defined
    • Partner claudins not identified
  2. 2007 Medium

    Resolved whether disease severity tracks with residual protein function, showing a dose-dependent relationship between claudin-16 activity and renal Ca2+/Mg2+ transport capacity.

    Evidence Mutant expression studies plus genotype-phenotype correlation across 71 FHHNC patients

    PMID:18003771

    Open questions at the time
    • Functional classification based on expression, not direct conductance measurement
    • Single study cohort
  3. 2008 Low

    Extended the structure-function map by establishing the second extracellular loop, not only the first, as essential for CLDN16 function.

    Evidence Domain-level mutation mapping in affected siblings

    PMID:18816383

    Open questions at the time
    • Single family case report with no in vitro reconstitution
    • No biophysical assay of loop function
  4. 2010 High

    Confirmed causal necessity in vivo and revealed the compensatory transcellular response when paracellular transport is lost.

    Evidence Cldn16 knockout mouse with urinary electrolyte, gene expression, and hormonal profiling

    PMID:20147368

    Open questions at the time
    • Molecular mechanism of compensatory gene induction unknown
    • Direct measurement of paracellular conductance not performed
    • Ion selectivity mechanism unresolved
  5. 2019 Medium

    Reclassified the molecular consequence of multiple exonic mutations, showing splicing disruption rather than coding change underlies a portion of pathogenic alleles.

    Evidence Minigene splicing assays for 12 CLDN16 exonic mutations

    PMID:30621608

    Open questions at the time
    • Splicing outcomes from minigenes not confirmed in patient tissue
    • Single lab
  6. 2025 Low

    Probed non-renal contexts, reporting cytoplasmic localization and pro-tumorigenic effects of CLDN16 across ovarian, thyroid, and pancreatic cancer cells.

    Evidence Pathway inhibitor/activator and knockdown phenotyping in OVCAR-3, PTC, and PAAD cell lines

    PMID:36889572 PMID:39996468 PMID:41407964

    Open questions at the time
    • Single-lab in vitro studies with no mechanistic epistasis
    • Connection to canonical tight-junction function unclear
    • No in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLDN16 achieves divalent-cation selectivity and which partner claudins or tight-junction proteins it requires to form a functional paracellular channel remains unresolved.
  • No reconstituted channel assay defining ion selectivity
  • Interacting claudins not identified in the corpus
  • No structural model of the channel

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-382551 Transport of small molecules 2 R-HSA-1500931 Cell-Cell communication 1
Complex memberships
tight junction

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CLDN16 (PCLN-1/paracellin-1) encodes a renal tight junction protein predominantly expressed in the thick ascending limb (TAL) of the loop of Henle, where it mediates paracellular reabsorption of divalent cations (Ca2+ and Mg2+). Mutations in the first extracellular loop (e.g., Leu151) disrupt the intercellular bridging function critical for paracellular conductance. Linkage analysis, mutational analysis, and mapping of mutations to functional protein domains (extracellular loop) European journal of human genetics : EJHG Medium 10878661
2007 Complete loss-of-function mutations in both CLDN16 alleles result in significantly earlier disease onset and faster GFR decline compared to mutations that retain partial protein function, establishing a dose-dependent relationship between residual claudin-16 activity and renal paracellular Ca2+/Mg2+ transport capacity. Expression studies of mutant proteins combined with clinical genotype-phenotype correlation in 71 FHHNC patients across 17+ mutations Journal of the American Society of Nephrology : JASN Medium 18003771
2010 Targeted deletion of murine Cldn16 causes hypercalciuria and hypomagnesemia, confirming that CLDN16 is required for renal paracellular Ca2+ and Mg2+ reabsorption in the thick ascending loop of Henle. Loss of CLDN16 triggers compensatory upregulation of transcellular Ca2+ and Mg2+ transport genes including Trpv5, Trpm6, calbindin-D9k, Cnnm2, and Atp13a4. Targeted gene knockout mouse model with urinary electrolyte measurements, gene expression profiling, and hormonal assays (PTH, 1,25(OH)2D3) American journal of physiology. Renal physiology High 20147368
2008 Mutations affecting the second extracellular loop of claudin-16 (e.g., Arg216Cys missense and a splice-site mutation truncating 64 amino acids in the second extracellular loop) cause complete loss of function of the protein, establishing the second extracellular loop as essential for CLDN16 function in paracellular transport. Mutation analysis with domain mapping and clinical loss-of-function correlation in affected siblings BMC nephrology Low 18816383
2019 Several CLDN16 exonic mutations previously classified as missense variants alter pre-mRNA splicing: mutations c.453G>T and c.446G>T inactivate exonic splicing enhancers and promote use of an internal cryptic acceptor splice site; c.571G>A causes partial exon 3 skipping; c.593G>C and c.593G>A disrupt the acceptor splice site of intron 3, causing complete exon 4 skipping. Minigene splicing assay for 12 CLDN16 exonic mutations BMC medical genetics Medium 30621608
2023 CLDN16 expression in high-grade serous ovarian cancer cells is upregulated via PKC, PI3K, and estrogen signaling pathways, and the protein localizes predominantly to the cytoplasm rather than at tight junctions in this cancer context. Immunoblotting, immunofluorescence, and pathway inhibitor/activator experiments in OVCAR-3 cells Experimental cell research Low 36889572
2025 CLDN16 knockdown in papillary thyroid cancer cells inhibits cell migration, invasion, and iodine uptake, demonstrating a pro-tumorigenic functional role for CLDN16 in PTC cell behavior. Knockdown experiments with migration, invasion, and iodine-uptake assays in PTC cells European journal of endocrinology Low 39996468
2025 CLDN16 knockdown in pancreatic adenocarcinoma cells enhances invasiveness and reduces apoptosis, identifying CLDN16 as a pro-tumorigenic factor in PAAD. Functional knockdown validation with invasion and apoptosis assays in pancreatic cancer cells Cellular and molecular life sciences : CMLS Low 41407964

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Journal of the American Society of Nephrology : JASN 88 18003771
2010 Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. American journal of physiology. Renal physiology 84 20147368
2000 Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 and is associated with mutations in the PCLN-1 gene. European journal of human genetics : EJHG 84 10878661
2012 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clinical journal of the American Society of Nephrology : CJASN 77 22422540
2003 Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC. Pediatric nephrology (Berlin, Germany) 30 14586675
2011 Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 28 21669885
2005 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations. Pediatric nephrology (Berlin, Germany) 25 16047219
2014 Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 24 25477417
2008 Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene. BMC nephrology 23 18816383
2006 Hydrochlorothiazide in CLDN16 mutation. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 16 16595585
2015 Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report. BMC nephrology 13 26136118
2006 A novel PCLN-1 gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype. Pediatric nephrology (Berlin, Germany) 13 17123117
2014 Two novel mutations of the CLDN16 gene cause familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. Clinical kidney journal 10 25852890
2003 Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 9 12584272
2020 Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Molecular genetics & genomic medicine 8 32869508
2013 A novel CLDN16 mutation in a large family with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. BMC research notes 8 24321194
2016 A novel mutation in CLDN16 results in rare familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in a Chinese family. Clinica chimica acta; international journal of clinical chemistry 7 27067446
2007 Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene. Journal of nephrology 7 17347984
2019 Exonic CLDN16 mutations associated with familial hypomagnesemia with hypercalciuria and nephrocalcinosis can induce deleterious mRNA alterations. BMC medical genetics 5 30621608
2021 Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features. Calcified tissue international 4 34761296
2023 Overexpression of CLDN16 in ovarian cancer is modulated by PI3K and PKC pathways. Experimental cell research 3 36889572
2020 Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in the CLDN16 Gene. Calcified tissue international 3 32710267
2018 A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings. The Turkish journal of pediatrics 3 30102483
2025 A new broom sweeps clean: CLDN16 surpasses the BRAF-V600E mutation as an unrivaled biomarker in papillary thyroid cancer. European journal of endocrinology 2 39996468
2023 Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family. Calcified tissue international 2 38078932
2022 A Novel Mutation in CLDN16 Gene Causing Familial Hypomagnesemia, Hypercalciuria, Nephrocalcinosis in An Iranian Family. Iranian journal of kidney diseases 2 35714216
2019 A novel CLDN16 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis
. Clinical nephrology 1 31232269
2019 In-Depth Bioinformatic Study of the CLDN16 Gene and Protein: Prediction of Subcellular Localization to Mitochondria. Medicina (Kaunas, Lithuania) 1 31357502
2026 X-linked hypophosphatemia in the presence of a CLDN16 variant: implications for renal handling and disease severity. JCEM case reports 0 41884086
2026 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN16/CLDN19 mutations in four Chinese families. Scientific reports 0 41896308
2025 Familial MEN1 Syndrome with Atypical Renal Features and a Coexisting CLDN16 Variant: A Case Series. Journal of clinical medicine 0 40807067
2025 Whole exome sequencing reveals a pathogenic homozygous CLDN16 mutation in a 17-year-old patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis: A case report. Medicine 0 40826740
2025 Recurrent Nephrolithiasis and Beyond: The Long Diagnostic Odyssey of a Case of CLDN16 Mutation. Clinical case reports 0 41306405
2025 Multi-omics analysis reveals cell adhesion molecules as key regulators of immune cell infiltration and adverse outcomes and in vitro validation of CLDN16 in pancreatic adenocarcinoma. Cellular and molecular life sciences : CMLS 0 41407964

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