Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome
Daphne J. Smits,
Jordy Dekker,
Hannie Douben,
Rachel Schot,
Helen Magee,
Somayeh Bakhtiari,
Katrin Koehler,
Angela Huebner,
Markus Schuelke,
Hossein Darvish,
Shohreh Vosoogh,
Abbas Tafakhori,
Melika Jameie,
Ehsan Taghiabadi,
Yana Wilson,
Margit Shah,
Marjon A. van Slegtenhorst,
Evita G. Medici-van den Herik,
Tjakko J. van Ham,
Michael C. Kruer,
Grazia M.S. Mancini
Affiliations
Daphne J. Smits
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; Corresponding author
Jordy Dekker
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Hannie Douben
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Rachel Schot
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Helen Magee
Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA; Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA
Somayeh Bakhtiari
Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA; Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA
Katrin Koehler
Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Angela Huebner
Department of Pediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Markus Schuelke
Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany
Hossein Darvish
Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
Shohreh Vosoogh
Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
Abbas Tafakhori
Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
Melika Jameie
Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
Ehsan Taghiabadi
Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
Yana Wilson
Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Cerebral Palsy Alliance Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Margit Shah
Department of Clinical Genetics, Children’s Hospital at Westmead, Sydney Children’s Hospitals Network, Westmead, NSW, Australia; Specialty of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
Marjon A. van Slegtenhorst
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Evita G. Medici-van den Herik
Department of Neurology, Section of Child Neurology, Erasmus University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Tjakko J. van Ham
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Michael C. Kruer
Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, USA; Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA
Grazia M.S. Mancini
Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Summary: 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.
