Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

Abstract

Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

“…28 Moreover, one missense and one nonsense mutations in MIB1 were identified previously and segregated each in two large dominant families with affected individuals with cardiomyopathy, but without ID. 36 Therefore, a contribution of the second mutation in MIB1 as potential modifier of the more severe phenotype is unlikely. The more severe phenotype may be caused by other yet unknown potential genetic modifier(s) or reflects the severe end of the clinical spectrum caused by WAC haploinsufficiency.…”

Left Ventricular Non-Compaction: Current Controversy and New Insights

“…In contrast, adult LVNC shows autosomal dominant inheritance and is associated with various other mutations most of which as previously stated are associated with dilated and hypertrophic cardiomyopathies [34,41,[45][46][47][48][49]. Additionally, families with adult LVNC demonstrate marked variation in phenotype [34,41,45,46,48]. Thus, it appears that infantile LVNC from G4.5 mutation is both genetically and phenotypically distinct from adult LVNC.…”

“…Targeted inactivation of MIB1 in mouse myocardium causes reduced NOTCH1 activity, expansion of compact myocardium to proliferative, immature trabeculae, resulting in LVNC phenotype [41]. To date this is the only genetic mutation found in human pedigrees that reliably causes LVNC phenotype in animal models with targeted inactivation.…”

“…Failure of the compaction process in utero is a longstanding proposed mechanism for development of LVNC and was initially thought to account for the phenotype of these patients [4,[35][36][37][38]40]. This hypothesis is supported by new evidence of an autosomal dominant form of LVNC in humans caused by a mutation in the mindbomb homolog1 (MIB1) gene encoding a protein which regulates cell proliferation and compaction of fetal myocardium [41]. Several lines of evidence, however, suggest that failure of compaction may not completely explain the finding of LVNC in many patients.…”

“…Thus, it appears that infantile LVNC from G4.5 mutation is both genetically and phenotypically distinct from adult LVNC. However, many autosomal dominant inherited forms of LVNC from other mutations can still result in severe symptom onset during infancy, so it is not conclusive that pediatric LVNC is a distinct disease entity [34,41,45,46,48]. Microvascular ischemia has been suggested as an additional factor in the pathophysiology of LVNC.…”