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

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.

SUBMITTER: Schneeberger PE

PROVIDER: S-EPMC7447524 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

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

Brain : a journal of neurology 20200801 8

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 facto ...[more]

PMID: 32761064

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Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.

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Dataset Information

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

Publications

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

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