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Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder

Authors :
David Gillis
Mutaz Sultan
Vardiella Meiner
Hagar Mor-Shaked
Orly Elpeleg
Tamar Harel
Mordechai Slae
Amir A Atawna
Nava Shaul-Lotan
Orli Halstuk
Bassam Abu-Libdeh
Source :
Eur J Hum Genet
Publication Year :
2020

Abstract

Rab proteins coordinate inter-organellar vesicle-mediated transport, facilitating intracellular communication, protein recycling, and signaling processes. Dysfunction of Rab proteins or their direct interactors leads to a wide range of diseases with diverse manifestations. We describe seven individuals from four consanguineous Arab Muslim families with an infantile-lethal syndrome, including failure to thrive (FTT), chronic diarrhea, neonatal respiratory distress, variable pituitary dysfunction, and distal arthrogryposis. Exome sequencing analysis in the independent families, followed by an internal gene-matching process using a local exome database, identified a homozygous splice-site variant in MADD (c.2816 + 1 G > A) on a common haplotype. The variant segregated with the disease in all available family members. Determination of cDNA sequence verified single exon skipping, resulting in an out-of-frame deletion. MADD encodes a Rab guanine nucleotide exchange factor (GEF), which activates RAB3 and RAB27A/27B and is thus a crucial regulator of neuromuscular junctions and endocrine secretory granule release. Moreover, MADD protects cells from caspase-mediated TNF-α-induced apoptosis. The combined roles of MADD and its downstream effectors correlate with the phenotypic spectrum of disease, and call for additional studies to confirm the pathogenic mechanism and to investigate possible therapeutic avenues through modulation of TNF-α signaling.

Details

ISSN :
14765438
Volume :
29
Issue :
6
Database :
OpenAIRE
Journal :
European journal of human genetics : EJHG
Accession number :
edsair.doi.dedup.....aeb226a445e25f8ce02de5dbea366bc3