title: MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.
abstract: MEDNIK syndrome-acronym for mental retardation, enteropathy, deafness, neuropathy, ichthyosis, keratodermia-is caused by AP1S1 gene mutations, encoding σ1A, the small subunit of the adaptor protein 1 complex, which plays a crucial role in clathrin coat assembly and mediates trafficking between trans-Golgi network, endosomes and the plasma membrane. MEDNIK syndrome was first reported in a few French-Canadian families sharing common ancestors, presenting a complex neurocutaneous phenotype, but its pathogenesis is not completely understood. A Sephardic-Jewish patient, carrying a new AP1S1 homozygous mutation, showed severe perturbations of copper metabolism with hypocupremia, hypoceruloplasminemia and liver copper accumulation, along with intrahepatic cholestasis. Zinc acetate treatment strikingly improved clinical conditions, as well as liver copper and bile-acid overload. We evaluated copper-related metabolites and liver function retrospectively in the original French-Canadian patient series. Intracellular copper metabolism and subcellular localization and function of copper pump ATP7A were investigated in patient fibroblasts. Copper metabolism perturbation and hepatopathy were confirmed in all patients. Studies in mutant fibroblasts showed abnormal copper incorporation and retention, reduced expression of copper-dependent enzymes cytochrome-c-oxidase and Cu/Zn superoxide dismutase, and aberrant intracellular trafficking of Menkes protein ATP7A, which normalized after rescue experiments expressing wild-type AP1S1 gene. We solved the pathogenetic mechanism of MEDNIK syndrome, demonstrating that AP1S1 regulates intracellular copper machinery mediated by copper-pump proteins. This multisystem disease is characterized by a unique picture, combining clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable by zinc acetate therapy, and can now be listed as a copper metabolism defect in humans. Our results may also contribute to understand the mechanism(s) of intracellular trafficking of copper pumps.
authors: Unit of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4 - 00165 Rome, Italy.
authors: Diego
authors: D
authors: Martinelli
authors: Lorena
authors: L
authors: Travaglini
authors: Christian A
authors: CA
authors: Drouin
authors: Irene
authors: I
authors: Ceballos-Picot
authors: Teresa
authors: T
authors: Rizza
authors: Enrico
authors: E
authors: Bertini
authors: Rosalba
authors: R
authors: Carrozzo
authors: Stefania
authors: S
authors: Petrini
authors: Pascale
authors: P
authors: de Lonlay
authors: Maya
authors: M
authors: El Hachem
authors: Laurence
authors: L
authors: Hubert
authors: Alexandre
authors: A
authors: Montpetit
authors: Giuliano
authors: G
authors: Torre
authors: Carlo
authors: C
authors: Dionisi-Vici
mesh_terms: D033961:Adaptor Protein Complex 1 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D003300:Copper / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008664:Metal Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D019345:Zinc Acetate / Q000627:therapeutic use*
chemical_list: C438983:AP1S1 protein, human; D033961:Adaptor Protein Complex 1; D034002:Adaptor Protein Complex sigma Subunits; D003300:Copper; D019345:Zinc Acetate