<i>MIB2</i>variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy

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

doi:10.1093/hmg/ddw365

Cited by 9 publications

(8 citation statements)

References 68 publications

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“…47 More recently, Piccolo et al studied carriers of MIB2 mutation and only every second carrier satisfied the currently accepted criteria for "noncompaction" and all carriers had benign "noncompaction". 48 As of yet, therefore, clinical genetics do not lend unequivocal support to the categorization of "noncompaction" as a distinct cardiomyopathy. Instead, some key findings can be considered in line with the notion of excessive trabeculation occurring as an epiphenomenon.…”

Section: "Noncompaction" Has a Multiplicity Of Anatomical Phenotypesmentioning

confidence: 98%

Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

Anderson

Jensen

Mohun³

et al. 2017

Canadian Journal of Cardiology

103

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The evidence is increasing that left ventricular noncompaction cardiomyopathy as it is currently defined does not represent a failure of compaction of pre-existing trabecular myocardium found during embryonic development to form the compact component of the ventricular walls. Neither is there evidence of which we are aware to favour the notion that the entity is a return to a phenotype seen in cold-blooded animals. It is also known that when seen in adults, the presence of excessive ventricular trabeculations does not portend a poor prognosis when the ejection fraction is normal, with the risks of complications such as arrhythmia and stroke being rare in this setting. It is also the case that images of "noncompaction" as provided from children or autopsy studies are quite different from the features observed clinically in asymptomatic adults with excessive trabeculation. Our review suggests that the presence of an excessively trabeculated left ventricular wall is not in itself a clinical entity. It is equally possible that the excessive trabeculation is no more than a bystander in the presence of additional lesions such as dilated cardiomyopathy, with the additional lesions being responsible for the reduced ejection fraction bringing a given patient to clinical attention. We, therefore, argue that the term "noncompaction cardiomyopathy" is misleading, because there is neither failure of compaction nor a cardiomyopathic process in most individuals that fulfill widely used diagnostic criteria.

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Section: "Noncompaction" Has a Multiplicity Of Anatomical Phenotypesmentioning

confidence: 98%

Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

Anderson

Jensen

Mohun³

et al. 2017

Canadian Journal of Cardiology

103

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“…To date, all mutations in JAG1 that are linked to Tetralogy of Fallot are missense alleles[309,311–313], which may have different consequences from the Alagille syndrome-linked mutations in this gene. In addition, dominant mutations (one nonsense and one missense, respectively) in MIB1 (OMIM #615092)[314] and MIB2 (OMIM #N/A)[315] have been linked to Left Ventricular Noncompaction (LVNC), a form of cardiomyopathy. Patients with a mutation in MIB2 also exhibit gastrointestinal phenotypes and have been classified as Ménétrier disease [315].…”

Section: Human Diseases Caused By Rare Mutations In Notch Pathway Genesmentioning

confidence: 99%

“…In addition, dominant mutations (one nonsense and one missense, respectively) in MIB1 (OMIM #615092)[314] and MIB2 (OMIM #N/A)[315] have been linked to Left Ventricular Noncompaction (LVNC), a form of cardiomyopathy. Patients with a mutation in MIB2 also exhibit gastrointestinal phenotypes and have been classified as Ménétrier disease [315]. In sum, cardiac defects are often associated with mutations affecting Notch signaling, which is likely due to the fact that Notch signaling plays a number of critical roles during cardiovascular development in vertebrates [316].…”

Section: Human Diseases Caused By Rare Mutations In Notch Pathway Genesmentioning

confidence: 99%

“…Currently (February 2017), of 149 genes that have been linked to Notch signaling in Drosophila melanogaster , 130 are conserved in human (87%) and 48 (37%) have human homologs that are linked to Mendelian diseases based on FlyBase[368], a manually curated database for Drosophila genetics and biology, and OMIM[292]. Identification of some of these disease genes was made possible through whole-exome sequencing [315,306,304,305,363,362]. As more and more exomes and genomes are sequenced in research and clinical diagnostic laboratories using high-throughput sequencing technologies[369–371], new human diseases that are caused by mutations in genes that have been previously linked to Notch signaling in flies are likely to be identified.…”

Section: Using Drosophila To Study Rare Functional Variants In Genes mentioning

confidence: 99%

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Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Salazar

Yamamoto

2018

Advances in Experimental Medicine and Biology

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Notch signaling research dates back to more than one hundred years, beginning with the identification of the Notch mutant in the fruit fly Drosophila melanogaster. Since then, research on Notch and related genes in flies has laid the foundation of what we now know as the Notch signaling pathway. In the 1990s, basic biological and biochemical studies of Notch signaling components in mammalian systems, as well as identification of rare mutations in Notch signaling pathway genes in human patients with rare Mendelian diseases or cancer, increased the significance of this pathway in human biology and medicine. In the 21st century, Drosophila and other genetic model organisms continue to play a leading role in understanding basic Notch biology. Furthermore, these model organisms can be used in a translational manner to study underlying mechanisms of Notch-related human diseases and to investigate the function of novel disease associated genes and variants. In this chapter, we first briefly review the major contributions of Drosophila to Notch signaling research, discussing the similarities and differences between the fly and human pathways. Next, we introduce several biological contexts in Drosophila in which Notch signaling has been extensively characterized. Finally, we discuss a number of genetic diseases caused by mutations in genes in the Notch signaling pathway in humans and we expand on how Drosophila can be used to study rare genetic variants associated with these and novel disorders. By combining modern genomics and state-of-the art technologies, Drosophila research is continuing to reveal exciting biology that sheds light onto mechanisms of disease.

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“…Compensatory function of Mib2 is not likely to be the cause of this lack of phenotype. Although it has been proposed that mutations in Mib2 could cause LVNC with Ménétrierlike gastropathy (Piccolo et al, 2017), evidence in mouse models shows that Mib2 is dispensable in heart development and its expression in embryonic development is almost absent (Koo et al, 2005a) and is not induced in Mib1 flox/flox ; Tnnt2-Cre hearts (Luxán et al, 2013). However, we confirmed the deleterious effect of both Mib1 R530X and Mib1 V943F mutations in heterozygosity at later stages of heart development by determining the increased prevalence of valve and septal defects when Mib1 mutations are introduced in a Notch1 heterozygous knock-out background.…”

Section: Mib1 Mutant Micementioning

confidence: 99%

Modelling the heterogeneity and complex inheritance of Left Ventricular Non-Compaction

Alvarez¹

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MIB2variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy

Cited by 9 publications

References 68 publications

Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

Key Questions Relating to Left Ventricular Noncompaction Cardiomyopathy: Is the Emperor Still Wearing Any Clothes?

Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases

Modelling the heterogeneity and complex inheritance of Left Ventricular Non-Compaction

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