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Biallelic Ndc1 Variants That Interfere With Aladin Binding Are Associated With Neuropathy and Triple A-Like Syndrome Publisher Pubmed



Smits DJ1 ; Dekker J1 ; Douben H1 ; Schot R1 ; Magee H2, 3 ; Bakhtiari S2, 3 ; Koehler K4 ; Huebner A4 ; Schuelke M5 ; Darvish H6 ; Vosoogh S7 ; Tafakhori A8 ; Jameie M8 ; Taghiabadi E9 Show All Authors
Authors
  1. Smits DJ1
  2. Dekker J1
  3. Douben H1
  4. Schot R1
  5. Magee H2, 3
  6. Bakhtiari S2, 3
  7. Koehler K4
  8. Huebner A4
  9. Schuelke M5
  10. Darvish H6
  11. Vosoogh S7
  12. Tafakhori A8
  13. Jameie M8
  14. Taghiabadi E9
  15. Wilson Y10, 11
  16. Shah M12, 13
  17. Van Slegtenhorst MA1
  18. Medicivan Den Herik EG14
  19. Van Ham TJ1
  20. Kruer MC2, 3
  21. Mancini GMS1
Show Affiliations
Authors Affiliations
  1. 1. Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, Rotterdam, 3015 GD, Netherlands
  2. 2. Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, 85016, AZ, United States
  3. 3. Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, 85004, AZ, United States
  4. 4. Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
  5. 5. Department of Neuropediatrics and NeuroCure Clinical Research Center, Charite-Universitatsmedizin Berlin, Berlin, Germany
  6. 6. Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
  7. 7. Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
  8. 8. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  11. 11. Cerebral Palsy Alliance Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  12. 12. Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospitals Network, Westmead, NSW, Australia
  13. 13. Specialty of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  14. 14. Department of Neurology, Section of Child Neurology, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, Rotterdam, 3015 GD, Netherlands

Source: Human Genetics and Genomics Advances Published:2024


Abstract

Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC. © 2024 The Author(s)
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