MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy

Pasquale Piccolo; Sergio Attanasio; Ilaria Secco; Riccardo Sangermano; Caterina Strisciuglio; Giuseppe Limongelli; Erasmo Miele; Margherita Mutarelli; Sandro Banfi; Vincenzo Nigro; Tirso Pons; Alfonso Valencia; Lorena Zentilin; Severo Campione; Gerardo Nardone; Ty C. Lynnes; Patricia B.S. Celestino-Soper; Katherine G. Spoonamore; Francesco P. D'Armiento; Mauro Giacca; Annamaria Staiano; Matteo Vatta; Chiara Collesi; Nicola Brunetti-Pierri

doi:10.1093/hmg/ddw365

MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy

Pasquale Piccolo, Sergio Attanasio, Ilaria Secco, Riccardo Sangermano, Caterina Strisciuglio, Giuseppe Limongelli, Erasmo Miele, Margherita Mutarelli, Sandro Banfi, Vincenzo Nigro, Tirso Pons, Alfonso Valencia, Lorena Zentilin, Severo Campione, Gerardo Nardone, Ty C. Lynnes, Patricia B.S. Celestino-Soper, Katherine G. Spoonamore, Francesco P. D'Armiento, Mauro GiaccaAnnamaria Staiano, Matteo Vatta, Chiara Collesi, Nicola Brunetti-Pierri^*

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Méné trier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Méné trier 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 Méné trier-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 Méné trier disease.

Original language	English
Pages (from-to)	33-43
Number of pages	11
Journal	Human Molecular Genetics
Volume	26
Issue number	1
DOIs	https://doi.org/10.1093/hmg/ddw365
Publication status	Published - 1 Jan 2017

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Piccolo, P., Attanasio, S., Secco, I., Sangermano, R., Strisciuglio, C., Limongelli, G., Miele, E., Mutarelli, M., Banfi, S., Nigro, V., Pons, T., Valencia, A., Zentilin, L., Campione, S., Nardone, G., Lynnes, T. C., Celestino-Soper, P. B. S., Spoonamore, K. G., D'Armiento, F. P., ... Brunetti-Pierri, N. (2017). MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy. Human Molecular Genetics, 26(1), 33-43. https://doi.org/10.1093/hmg/ddw365

@article{a535f8ceeaec4adbb1d25df6d895cb77,

title = "MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with M{\'e}n{\'e} trier-like gastropathy",

abstract = "We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling M{\'e}n{\'e} trier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. M{\'e}n{\'e} trier 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 M{\'e}n{\'e} trier-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 M{\'e}n{\'e} trier disease.",

author = "Pasquale Piccolo and Sergio Attanasio and Ilaria Secco and Riccardo Sangermano and Caterina Strisciuglio and Giuseppe Limongelli and Erasmo Miele and Margherita Mutarelli and Sandro Banfi and Vincenzo Nigro and Tirso Pons and Alfonso Valencia and Lorena Zentilin and Severo Campione and Gerardo Nardone and Lynnes, {Ty C.} and Celestino-Soper, {Patricia B.S.} and Spoonamore, {Katherine G.} and D'Armiento, {Francesco P.} and Mauro Giacca and Annamaria Staiano and Matteo Vatta and Chiara Collesi and Nicola Brunetti-Pierri",

year = "2017",

month = jan,

day = "1",

doi = "10.1093/hmg/ddw365",

language = "English",

volume = "26",

pages = "33--43",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "1",

}

Piccolo, P, Attanasio, S, Secco, I, Sangermano, R, Strisciuglio, C, Limongelli, G, Miele, E, Mutarelli, M, Banfi, S, Nigro, V, Pons, T, Valencia, A, Zentilin, L, Campione, S, Nardone, G, Lynnes, TC, Celestino-Soper, PBS, Spoonamore, KG, D'Armiento, FP, Giacca, M, Staiano, A, Vatta, M, Collesi, C & Brunetti-Pierri, N 2017, 'MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy', Human Molecular Genetics, vol. 26, no. 1, pp. 33-43. https://doi.org/10.1093/hmg/ddw365

TY - JOUR

T1 - MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy

AU - Piccolo, Pasquale

AU - Attanasio, Sergio

AU - Secco, Ilaria

AU - Sangermano, Riccardo

AU - Strisciuglio, Caterina

AU - Limongelli, Giuseppe

AU - Miele, Erasmo

AU - Mutarelli, Margherita

AU - Banfi, Sandro

AU - Nigro, Vincenzo

AU - Pons, Tirso

AU - Valencia, Alfonso

AU - Zentilin, Lorena

AU - Campione, Severo

AU - Nardone, Gerardo

AU - Lynnes, Ty C.

AU - Celestino-Soper, Patricia B.S.

AU - Spoonamore, Katherine G.

AU - D'Armiento, Francesco P.

AU - Giacca, Mauro

AU - Staiano, Annamaria

AU - Vatta, Matteo

AU - Collesi, Chiara

AU - Brunetti-Pierri, Nicola

PY - 2017/1/1

Y1 - 2017/1/1

N2 - We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Méné trier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Méné trier 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 Méné trier-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 Méné trier disease.

AB - We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Méné trier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Méné trier 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 Méné trier-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 Méné trier disease.

UR - http://www.scopus.com/inward/record.url?scp=85018518784&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw365

DO - 10.1093/hmg/ddw365

M3 - Article

C2 - 28013292

AN - SCOPUS:85018518784

SN - 0964-6906

VL - 26

SP - 33

EP - 43

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Méné trier-like gastropathy

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