MRAS in coronary artery disease-Unchartered territory.

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.

A homozygous nonsense variant in DYM underlies Dyggve-Melchior-Clausen syndrome associated with ectodermal features.

Dyggve melchior clausen syndrome (DMC, MIM 223800) is a very rare autosomal recessive form of skeletal dysplasia associated with various degrees of mental retardation. It is characterized by a progressive spondyloepimetaphyseal dysplasia (SEMD) with disproportionate short stature, generalized platyspondyly and lacy iliac crest. Here, we report characterization of large consanguineous family segregating DMC in autosomal recessive manner. Scanning SNP-based human genome identified a 5.3 Mb homozygous region on chromosome 18q21.1-q21.2. Sanger sequencing of the DYM gene, located in the homozygous region, revealed a novel homozygous nonsense variant [c.59 T > A; p.(Leu20*)] in affected members of the family. Analysis of the mRNA, extracted from hair follicles of an affected individual, suggested non-sense mediated decay (NMD) of the truncated transcript. This is the first nonsense and fourth loss of function variant in the DYM gene, causing DMC, reported in the Pakistani population. This study not only extended spectrum of the mutations in the DYM gene but will also facilitate diagnosis of similar other cases in Pakistani population.

Beyond the Basics: Unraveling the Complexity of Coronary Artery Calcification.

Coronary artery calcification (CAC) is mainly associated with coronary atherosclerosis, which is an indicator of coronary artery disease (CAD). CAC refers to the accumulation of calcium phosphate deposits, classified as micro- or macrocalcifications, that lead to the hardening and narrowing of the coronary arteries. CAC is a strong predictor of future cardiovascular events, such as myocardial infarction and sudden death. Our narrative review focuses on the pathophysiology of CAC, exploring its link to plaque vulnerability, genetic factors, and how race and sex can affect the condition. We also examined the connection between the gut microbiome and CAC, and the impact of genetic variants on the cellular processes involved in vascular calcification and atherogenesis. We aimed to thoroughly analyze the existing literature to improve our understanding of CAC and its potential clinical and therapeutic implications.

A novel insertion and deletion mutation in the BHLHA9 underlies polydactyly and mesoaxial synostotic syndactyly with phalangeal reduction.

Mesoaxial syndactyly is characterized by fusion of the central digits. The disorder segregates in autosomal recessive pattern and mapped on human chromosome 17p13.3. Homozygous missense mutations in the BHLHA9 have been reported to cause mesoaxial synostotic syndactyly with phalangeal reduction (MSSD). In the present study, we have investigated a family segregating mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) in autosomal recessive manner. Genotyping using microsatellite markers followed by Sanger sequencing revealed a homozygous deletion and insertion mutation (NM_001164405: c.252_270delinsGCA; p.(Phe85Glufs*108)) in the BHLHA9 gene in affected individuals of the family. This study reports the first frameshift mutation in the BHLHA9 causing mesoaxial synostotic syndactyly and phalangeal reduction.