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

August 01, 2020

Pauline E Schneeberger 1 , Fanny Kortüm 1 , Georg Christoph Korenke 2 , Malik Alawi 3 , René Santer 4 , Mathias Woidy 4 , Daniela Buhas 5 6 , Stephanie Fox 5 6 , Jane Juusola 7 , Majid Alfadhel 8 9 10 , Bryn D Webb 11 12 13 , Emanuele G Coci 14 15 , Rami Abou Jamra 16 , Manuela Siekmeyer 17 , Saskia Biskup 18 , Corina Heller 18 , Esther M Maier 19 , Poupak Javaher-Haghighi 20 , Maria F Bedeschi 21 , Paola F Ajmone 22 , Maria Iascone 23 , Hilde Peeters 24 , Katleen Ballon 25 , Jaak Jaeken 26 , Aroa Rodríguez Alonso 27 , María Palomares-Bralo 28 , Fernando Santos-Simarro 28 , Marije E C Meuwissen 29 , Diane Beysen 30 , R Frank Kooy 31 , Henry Houlden 32 , David Murphy 32 , Mohammad Doosti 33 , Ehsan G Karimiani 33 34 , Majid Mojarrad 35 36 37 , Reza Maroofian 32 , Lenka Noskova 38 , Stanislav Kmoch 38 , Tomas Honzik 39 , Heidi Cope 40 , Amarilis Sanchez-Valle 41 , Undiagnosed Diseases Network; Bruce D Gelb 11 12 13 , Ingo Kurth 42 43 , Maja Hempel 1 , Kerstin Kutsche 1


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.

Keywords: DENN; HSAN; intellectual disability; multisystem; whole-exome sequencing.