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

TY - JOUR

T1 - Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

AU - Schneeberger, Pauline E

AU - Kortüm, Fanny

AU - Korenke, Georg Christoph

AU - Alawi, Malik

AU - Santer, René

AU - Woidy, Mathias

AU - Buhas, Daniela

AU - Fox, Stephanie

AU - Juusola, Jane

AU - Alfadhel, Majid

AU - Webb, Bryn D

AU - Coci, Emanuele G

AU - Abou Jamra, Rami

AU - Siekmeyer, Manuela

AU - Biskup, Saskia

AU - Heller, Corina

AU - Maier, Esther M

AU - Javaher-Haghighi, Poupak

AU - Bedeschi, Maria F

AU - Ajmone, Paola F

AU - Iascone, Maria

AU - Peeters, Hilde

AU - Ballon, Katleen

AU - Jaeken, Jaak

AU - Rodríguez Alonso, Aroa

AU - Palomares-Bralo, María

AU - Santos-Simarro, Fernando

AU - Meuwissen, Marije E C

AU - Beysen, Diane

AU - Kooy, R Frank

AU - Houlden, Henry

AU - Murphy, David

AU - Doosti, Mohammad

AU - Karimiani, Ehsan G

AU - Mojarrad, Majid

AU - Maroofian, Reza

AU - Noskova, Lenka

AU - Kmoch, Stanislav

AU - Honzik, Tomas

AU - Cope, Heidi

AU - Sanchez-Valle, Amarilis

AU - Undiagnosed Diseases Network

AU - Gelb, Bruce D

AU - Kurth, Ingo

AU - Hempel, Maja

AU - Kutsche, Kerstin

N1 - © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

U2 - 10.1093/brain/awaa204

DO - 10.1093/brain/awaa204

M3 - SCORING: Journal article

C2 - 32761064

VL - 143

SP - 2437

EP - 2453

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 8

ER -