Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Pauline E Schneeberger; Fanny Kortüm; Georg Christoph Korenke; Malik Alawi; René Santer; Mathias Woidy; Daniela Buhas; Stephanie Fox; Jane Juusola; Majid Alfadhel; Bryn D Webb; Emanuele G Coci; Rami Abou Jamra; Manuela Siekmeyer; Saskia Biskup; Corina Heller; Esther M Maier; Poupak Javaher-Haghighi; Maria F Bedeschi; Paola F Ajmone; Maria Iascone; Hilde Peeters; Katleen Ballon; Jaak Jaeken; Aroa Rodríguez Alonso; María Palomares-Bralo; Fernando Santos-Simarro; Marije E C Meuwissen; Diane Beysen; R Frank Kooy; Henry Houlden; David Murphy; Mohammad Doosti; Ehsan G Karimiani; Majid Mojarrad; Reza Maroofian; Lenka Noskova; Stanislav Kmoch; Tomas Honzik; Heidi Cope; Amarilis Sanchez-Valle; Bruce D Gelb; Ingo Kurth; Maja Hempel; Kerstin Kutsche

doi:10.1093/brain/awaa204

Back

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Journal article

Peer reviewed

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Pauline E Schneeberger, Fanny Kortüm, Georg Christoph Korenke, Malik Alawi, René Santer, Mathias Woidy, Daniela Buhas, Stephanie Fox, Jane Juusola, Majid Alfadhel, …

Brain (London, England : 1878), Vol.143(8), pp.2437-2453

2020-08-01

DOI: https://doi.org/10.1093/brain/awaa204

PMID: 32761064

Abstract

Guanine Nucleotide Exchange Factors - genetics

Phenotype

Humans

Developmental Disabilities - genetics

Signal Transduction - genetics

Mutation

Death Domain Receptor Signaling Adaptor Proteins - genetics

Nervous System Diseases - genetics

Protein Transport - genetics

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.

Metrics

8 Record Views

16 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.96 Cell Biology; 1.96.302 Exocytosis
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder
Creators: Pauline E Schneeberger - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Fanny Kortüm - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Georg Christoph Korenke - Klinik für Neuropädiatrie und angeborene Stoffwechselerkrankungen, Klinikum Oldenburg, Oldenburg, Germany
Malik Alawi - Bioinformatics Core Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
René Santer - Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Mathias Woidy - Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Daniela Buhas - Human Genetics Department, McGill University, Montreal, Canada
Stephanie Fox - Human Genetics Department, McGill University, Montreal, Canada
Jane Juusola - GeneDx, Gaithersburg, USA
Majid Alfadhel - King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
Bryn D Webb - Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Emanuele G Coci - Department of Pediatrics, Prignitz Hospital, Brandenburg Medical School, Germany
Rami Abou Jamra - Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany
Manuela Siekmeyer - Universitätsklinikum Leipzig - AöR, University of Leipzig, Hospital for Children and Adolescents, Leipzig, Germany
Saskia Biskup - CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
Corina Heller - CeGaT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
Esther M Maier - Dr. von Hauner Children's Hospital, University of Munich, Munich, Germany
Poupak Javaher-Haghighi - Medicover Humangenetik Hannover, Hanover, Germany
Maria F Bedeschi - Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Paola F Ajmone - Child and Adolescent Neuropsychiatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
Maria Iascone - Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy
Hilde Peeters - Center for Human Genetics, KU Leuven, Leuven, Belgium
Katleen Ballon - Centre for Developmental Disabilities, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Jaak Jaeken - Center for Metabolic Diseases, KU Leuven, Leuven, Belgium
Aroa Rodríguez Alonso - Unidad de Patología Compleja, Servicio de Pediatría, Hospital Universitario La Paz, Madrid, Spain
María Palomares-Bralo - Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
Fernando Santos-Simarro - Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
Marije E C Meuwissen - Center of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium
Diane Beysen - Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium
R Frank Kooy - Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
Henry Houlden - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
David Murphy - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
Mohammad Doosti - Next Generation Genetic Polyclinic, Mashhad, Iran
Ehsan G Karimiani - Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University, London, UK
Majid Mojarrad - Genetic Center of Khorasan Razavi, Mashhad, Iran
Reza Maroofian - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
Lenka Noskova - Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Stanislav Kmoch - Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
Tomas Honzik - Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
Heidi Cope - Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
Amarilis Sanchez-Valle - Division of Genetics and Metabolism, College of Medicine, University of South Florida, Tampa, Florida, USA
Bruce D Gelb - Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Ingo Kurth - Institute of Human Genetics, Jena University Hospital, Jena, Germany
Maja Hempel - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Kerstin Kutsche - Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Publication Details: Brain (London, England : 1878), Vol.143(8), pp.2437-2453
Publisher: England
Grant note: S10 OD018522 / NIH HHS S10 OD026880 / NIH HHS U01 HG007942 / NHGRI NIH HHS U01 HG007672 / NHGRI NIH HHS
Language: English
Resource Type: Journal article
PMID: 32761064
Record Identifier: 991031577527102976