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

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Systems Biology

Background:

• Pleiotropic diseases affect multiple organ systems with diverse clinical manifestations.
• Mitogen-activated protein kinase (MAPK) activating death domain protein (MADD) regulates key cellular functions including signaling and cell death.
• Understanding MADD's role is crucial for deciphering complex genetic disorders.

Observation:

• A cohort of 23 patients with biallelic MADD variants presented with unique neurological, endocrine, exocrine, and hematological findings.
• Patients were categorized into two groups based on phenotype severity, with Group 1 exhibiting severe multi-system involvement and Group 2 primarily neurological symptoms.
• Analysis revealed aberrant MADD transcripts and a significant reduction or loss of MADD protein in patient-derived cells.

Findings:

• MADD deficiency leads to impaired tumor necrosis factor-α (TNF-α)-induced signaling, evidenced by reduced ERK1/2 phosphorylation.
• Patient cells showed enhanced apoptosis due to increased caspase-3 and -7 activation.
• Defects in epidermal growth factor endocytosis were identified, indicating compromised vesicular trafficking.

Implications:

• MADD deficiency underlies a severe pleiotropic disorder impacting multiple cellular pathways.
• The findings highlight MADD's critical role in TNF-α signaling, apoptosis regulation, and endocytosis.
• This research expands our understanding of MADD's physiological functions in the nervous, endocrine, and exocrine systems.