A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction

Abstract

Cardiomyopathies are a group of common heart disorders that affect numerous people worldwide. Left ventricular non-compaction (LVNC) is a structural disorder of the ventricular wall, categorized as a type of cardiomyopathy that mostly caused by genetic disorders. Genetic variations are underlying causes of developmental deformation of the heart wall and the resultant contractile insufficiency. Here, we investigated a family with several affected members exhibiting LVNC phenotype. By whole-exome sequencing (WES) of three affected members, we identified a novel heterozygous missense variant (c.1963C>A:p.Leu655Met) in the gene encoding myosin heavy chain 7 (MYH7). This gene is evolutionary conserved among different organisms. We identified MYH7 as a highly enriched myosin, compared to other types of myosin heavy chains, in skeletal and cardiac muscles. Furthermore, MYH7 was among a few classes of MYH in mouse heart that highly expresses from early embryonic to adult stages. In silico predictions showed an altered actin-myosin binding, resulting in weaker binding energy that can cause LVNC. Moreover, CRISPR/Cas9 mediated MYH7 knockout in zebrafish caused impaired cardiovascular development. Altogether, these findings provide the first evidence for involvement of p.Leu655Met missense variant in the incidence of LVNC, most probably through actin-myosin binding defects during ventricular wall morphogenesis.

Placental Inflammation Leads to Abnormal Embryonic Heart Development

“…Furthermore, recent data suggest that downregulation in the Myh7 gene is associated with LVNC. 31 Thus, the downregulation in Myh7 expression in NDPI embryonic hearts could account for the LVNC-like phenotype.…”

“…Furthermore, recent data suggest that downregulation in the Myh7 gene is associated with LVNC. 31 Thus, the downregulation in Myh7 expression in NDPI embryonic hearts could account for the LVNC-like phenotype. There were significant increases in gene expression of Gata4, Meft2c, Hey2, and Nppa in both CCR2 +/− control and CCR2 +/− NDPI embryonic hearts compared with controls (Figure S8E).…”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…Much of the work has focused on the role of specific genes in organ formation and function, including the lens [ 99 ], retina [ 100 , 101 , 102 ], optic neurons [ 103 , 104 ], ocular vessels [ 105 , 106 ], inner ear [ 107 , 108 , 109 , 110 , 111 ], vestibular apparatus [ 111 ], otoliths [ 112 ], brain [ 89 , 113 , 114 , 115 , 116 , 117 ], neural tissue [ 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ] and nervous system [ 128 , 129 , 130 ], heart [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ], cardiomyocytes [ 140 , 141 , 142 , 143 ], including cardiovascular rate control [ 144 , 145 ], blood vessels [ 146 , 147 ,…”

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

“…MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a key sarcomere protein that binds both actin and myosin [70]. MYH7 is a sarcomeric gene encoding myosin heavy chain beta (MHC-β) and plays a crucial role in the contraction of muscle fibres [71,72]. It is responsible for the ATP-dependent sliding movement of actin and myosin filaments which results in contraction [73].…”