2. Academic Validation
  3. Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome

Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome

  • Am J Hum Genet. 2019 Nov 7;105(5):1016-1022. doi: 10.1016/j.ajhg.2019.09.020.
Hessa S Alsaif 1,  Mohammad Al-Owain 2,  Martin E Barrios-Llerena 3,  Ghada Gosadi 4,  Yousef Binamer 5,  David Devadason 6,  Jane Ravenscroft 7,  Mohnish Suri 8,  Fowzan S Alkuraya 9
Affiliations

Affiliations

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 2 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
  • 3 Proteomics and Mass Spectrometry, Bioscience Core Labs, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia.
  • 4 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 5 Department of Dermatology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 6 Department of Paediatric Gastroenterology, Nottingham Children's Hospital, Nottingham University Hospitals, Queen's Medical Centre, Nottingham NG72UH, United Kingdom.
  • 7 Department of Paediatric Dermatology, Nottingham Children's Hospital, Nottingham University Hospitals, Queen's Medical Centre, Nottingham NG72UH, United Kingdom.
  • 8 Clinical Genetics Service, Nottingham University Hospitals, City Hospital Campus, Nottingham NG51PB, United Kingdom. Electronic address: [email protected].
  • 9 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: [email protected].
PMID: 31630791 DOI: 10.1016/j.ajhg.2019.09.020
Abstract

MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is an autosomal-recessive disorder caused by bi-allelic mutations in AP1S1, encoding the small σ subunit of the AP-1 complex. Central to the pathogenesis of MEDNIK syndrome is abnormal AP-1-mediated trafficking of copper transporters; this abnormal trafficking results in a hybrid phenotype combining the copper-deficiency-related characteristics of Menkes disease and the copper-toxicity-related characteristics of Wilson disease. We describe three individuals from two unrelated families in whom a MEDNIK-like phenotype segregates with two homozygous null variants in AP1B1, encoding the large β subunit of the AP-1 complex. Similar to individuals with MEDNIK syndrome, the affected individuals we report display abnormal copper metabolism, evidenced by low plasma copper and ceruloplasmin, but lack evidence of copper toxicity in the liver. Functional characterization of fibroblasts derived from affected individuals closely resembles the abnormal ATP7A trafficking described in MEDNIK syndrome both at baseline and in response to copper treatment. Taken together, our results expand the list of inborn errors of copper metabolism.

Keywords

AP-1; ATP7A; Menkes; clathrin coated vesicles (CCV); copper; trafficking.

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