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

Hum Mol Genet. 2006 Apr 1;15(7):1049-58. doi: 10.1093/hmg/ddl020. Epub 2006 Feb 24.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Calcium Metabolism Disorders / blood
  • Calcium Metabolism Disorders / genetics
  • Calcium Metabolism Disorders / metabolism*
  • Calcium Metabolism Disorders / urine
  • Cells, Cultured
  • Child, Preschool
  • Clathrin / metabolism
  • Claudins
  • Dogs
  • Endocytosis* / physiology
  • Endoplasmic Reticulum / metabolism
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Homozygote
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Lysosomes / metabolism
  • Magnesium Deficiency / blood
  • Magnesium Deficiency / genetics*
  • Magnesium Deficiency / metabolism
  • Magnesium Deficiency / urine
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Mutation*
  • Nephrocalcinosis / genetics*
  • Nephrocalcinosis / metabolism
  • Nephrocalcinosis / urine
  • Phenotype
  • Proteasome Endopeptidase Complex / metabolism
  • Transfection

Substances

  • Clathrin
  • Claudins
  • Membrane Proteins
  • claudin 16
  • Proteasome Endopeptidase Complex