title: MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy.
abstract: We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in MIB2, a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of HES1 and NOTCH3 expression reflecting alteration of NOTCH signalling. Because mutations of MIB1, the homolog of MIB2, have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the MIB2 variant. Finally, we identified an additional MIB2 variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both MIB2 variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.In conclusion, we report the first example of left ventricular hypertrabeculation/LVNC with germline MIB2 variants resulting in altered NOTCH signalling that might be associated with a gastropathy clinically overlapping with Ménétrier disease.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Piccolo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Attanasio
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Secco
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sangermano
authors.affiliation: Department of Woman, Child and General and Specialized Surgery, Second University of Naples, Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Strisciuglio
authors.affiliation: Department of Cardiothoracic Sciences, Monaldi Hospital, Second University of Naples, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Limongelli
authors.affiliation: Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Miele
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Tirso
authors.initials: T
authors.lastname: Pons
authors.affiliation: Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Severo
authors.initials: S
authors.lastname: Campione
authors.affiliation: Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Nardone
authors.affiliation: Department of Medical and Molecular Genetics.
authors.forename: Ty C
authors.initials: TC
authors.lastname: Lynnes
authors.affiliation: Department of Medical and Molecular Genetics.
authors.forename: Patricia B S
authors.initials: PB
authors.lastname: Celestino-Soper
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Spoonamore
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: D'Armiento
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Staiano
authors.affiliation: Department of Medical and Molecular Genetics.|Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.|Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Collesi
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D059472:Exome / Q000235:genetics; D005260:Female; D005758:Gastritis, Hypertrophic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D051381:Rats; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013272:Stomach Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D051880:Receptors, Notch; C478156:MIB2 protein, human; D044767:Ubiquitin-Protein Ligases