title: 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.
abstract: Mutations in the gene for Claudin-16 (CLDN16) are linked to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a renal Mg2+ and Ca2+ wasting disorder that leads to progressive kidney failure. More than 20 mutations have been identified in CLDN16, which, with a single exception, affect one of two extracellular loops or one of four transmembrane domains of the encoded protein. Here, we describe a novel missense mutation, Cldn16 L203X, which deletes the entire C-terminal cytosolic domain of the protein. Surface expression of Cldn16 L203X is strongly reduced and the protein is instead found in the endoplasmic reticulum (ER) and lysosomes. ER-retained Cldn16 L203X is subject to proteasomal degradation. Cldn16 L203X present in lysosomes reaches this compartment following transport to the plasma membrane and endocytosis. Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X. Thus, endocytosis inhibitors may provide a novel therapeutic approach for FHHNC patients carrying particular Cldn16 mutations.
authors.affiliation: Department of Pediatric Nephrology and Center for Cardiovascular Research, Charité, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: P Jaya
authors.initials: PJ
authors.lastname: Kausalya
authors.forename: Iwan C
authors.initials: IC
authors.lastname: Meij
authors.forename: Walter
authors.initials: W
authors.lastname: Hunziker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002128:Calcium Metabolism Disorders / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D002478:Cells, Cultured; D002675:Child, Preschool; D002966:Clathrin / Q000378:metabolism; D057167:Claudins; D004285:Dogs; D004705:Endocytosis / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008275:Magnesium Deficiency / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009397:Nephrocalcinosis / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014162:Transfection
chemical_list: D002966:Clathrin; D057167:Claudins; D008565:Membrane Proteins; C502010:claudin 16; D046988:Proteasome Endopeptidase Complex