Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder
Brain, vol. 143, pp. 2437–2453
Abstract
In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
Authors 96
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Affiliation as printed
Klinik für Neuropädiatrie und angeborene Stoffwechselerkrankungen, Klinikum Oldenburg, Oldenburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Bioinformatics Core Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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McGill University Health Centre · McGill University
Affiliation as printed
Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada
Human Genetics Department, McGill University, Montreal, Canada
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Affiliation as printed
GeneDx, Gaithersburg, USA
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King Saud bin Abdulaziz University for Health Sciences · King Abdulaziz Medical City · King Abdullah International Medical Research Center · National Guard Health Affairs
Affiliation as printed
Division of Genetics, Department of Pediatrics, King Abdullah specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
Division of Genetics, Department of Pediatrics, King Abdullah specialized Children's Hospital, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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University Hospitals of the Ruhr-University of Bochum · Universitätsklinikum Brandenburg an der Havel · Ruhr University Bochum
Affiliation as printed
Department for Neuropediatrics, University Children’s Hospital, Ruhr University Bochum, Bochum, Germany
Department of Pediatrics, Prignitz Hospital, Brandenburg Medical School, Germany
Department for Neuropediatrics, University Children's Hospital, Ruhr University Bochum, Bochum, Germany
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany
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University Hospital Leipzig · Leipzig University
Affiliation as printed
Universitätsklinikum Leipzig - AöR, University of Leipzig, Hospital for Children and Adolescents, Leipzig, Germany
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Praxis für Humangenetik Tübingen · CeGaT (Germany)
Affiliation as printed
CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
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Praxis für Humangenetik Tübingen · CeGaT (Germany)
Affiliation as printed
CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
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Ludwig-Maximilians-Universität München
Affiliation as printed
Dr. von Hauner Children’s Hospital, University of Munich, Munich, Germany
Dr. von Hauner Children's Hospital, University of Munich, Munich, Germany
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Affiliation as printed
Medicover Humangenetik Hannover, Hanover, Germany
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Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Affiliation as printed
Medical Genetic Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Affiliation as printed
Child and Adolescent Neuropsychiatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
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Affiliation as printed
Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy
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Affiliation as printed
Center for Human Genetics, KU Leuven, Leuven, Belgium
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Affiliation as printed
Centre for Developmental Disabilities, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
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Affiliation as printed
Center for Metabolic Diseases, KU Leuven, Leuven, Belgium
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Affiliation as printed
Unidad de Patología Compleja, Servicio de Pediatría, Hospital Universitario La Paz, Madrid, Spain
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases
Affiliation as printed
Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
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Affiliation as printed
Center of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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National Hospital for Neurology and Neurosurgery · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
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National Hospital for Neurology and Neurosurgery · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
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Affiliation as printed
Next Generation Genetic Polyclinic, Mashhad, Iran
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University of London · St George's, University of London
Affiliation as printed
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George’s, University, London, UK
Next Generation Genetic Polyclinic, Mashhad, Iran
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University, London, UK
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Mashhad University of Medical Sciences
Affiliation as printed
Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Genetic Center of Khorasan Razavi, Mashhad, Iran
Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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National Hospital for Neurology and Neurosurgery · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
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Affiliation as printed
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Affiliation as printed
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Charles University · General University Hospital in Prague
Affiliation as printed
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
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Affiliation as printed
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
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Affiliation as printed
Division of Genetics and Metabolism, College of Medicine, University of South Florida, Tampa, Florida, USA
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McGill University Health Centre · McGill University
Affiliation as printed
Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, Canada
Human Genetics Department, McGill University, Montreal, Canada
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Affiliation as printed
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
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