👤 Hala F Zaki

Familial Hypercholesterolemia (FH) is a major risk factor for premature Coronary Artery Disease (CAD). Genetic testing is the gold standard for FH diagnosis. The purpose of this Observational Analytical Cross-sectional study was to estimate the proportion of genetically confirmed Familial Hypercholesterolemia in Patients with premature Coronary Artery Disease in a cohort of Egyptian patients. Next generation sequencing (NGS) was conducted for 7 genes (LDLR, PCSK9, APOB, APOE, ABCG5, ABCG8 and LDLRAP1) commonly associated with FH in 94 patients with Premature CAD from 2 tertiary hospitals in Cairo and Alexandria, Egypt. Individuals were clinically assessed using the Dutch Lipid Network criteria and genetically-confirmed FH prevalence was analyzed. Fourteen patients had pathogenic or likely pathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes. Three patients had homozygous autosomal dominant FH and another 3 patients had autosomal recessive hypercholesterolemia. In addition, 10 patients had rare variants of uncertain significance in LDLR, APOB, APOE, ABCG5 and ABCG8 genes. The prevalence of genetically confirmed FH in premature CAD (PCAD) patients in this study was found to be 14.89%. The Dutch Lipid Clinic Network (DLCN) scoring system is suggested as a good screening tool for familial hypercholesterolemia but confirmatory genetic testing is essential for the accurate diagnosis and management of the patients. In Egypt, the high rate of consanguinity contributes to the high prevalence of both homozygous autosomal dominant and recessive FH. Show less

Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. Show less

Defective β-catenin signaling is accompanied with compensatory neurogenesis process that may pave to anxiety. β-Catenin has a distinct role in alleviating anxiety in adolescence; however, it undergoes degradation by the degradation complex Axin and APC. Vilazodone (VZ) is a fast, effective antidepressant with SSRI activity and 5-HT Show less

The mutual interplay between neuroinflammation, synaptic plasticity, and autophagy has piqued researchers' interest, particularly when it comes to linking their impact and relationship to cognitive deficits. Being able to reduce inflammation and apoptosis, melatonin has shown to have positive neuroprotective effects; that is why we thought to check the possible role of agomelatine (AGO) as a promising candidate that could have a positive impact on cognitive deficits. In the current study, AGO (40 mg/kg/day, p.o., 7 days) successfully ameliorated the cognitive and learning disabilities caused by lipopolysaccharide (LPS) in rats (250 μg/kg/day, i.p., 7 days). This positive impact was supported by improved histopathological findings and improved spatial memory as assessed using Morris water maze. AGO showed a strong ability to control BACE1 activity and to rein in the hippocampal amyloid beta (Aβ) deposition. Also, it improved neuronal survival, neuroplasticity, and neurogenesis by boosting BDNF levels and promoting its advantageous effects and by reinforcing the pTrkB expression. In addition, it upregulated the pre- and postsynaptic neuroplasticity biomarkers resembled in synapsin I, synaptophysin, and PSD-95. Furthermore, AGO showed a modulatory action on Sortilin-related receptor with A-type repeats (SorLA) pathway and adjusted autophagy. It is noteworthy that all of these actions were abolished by administering PD98059 a MEK/ERK pathway inhibitor (0.3 mg/kg/day, i.p., 7 days). In conclusion, AGO administration significantly improves memory and learning disabilities associated with LPS administration by modulating the ERK/SorLA/BDNF/TrkB signaling pathway parallel to its capacity to adjust the autophagic process. Show less

Autophagy and apoptosis are cellular processes that maintain cellular homeostasis and remove damaged or aged organelles or aggregated and misfolded proteins. Stress factors initiate the signaling pathways common to autophagy and apoptosis. An imbalance in the autophagy and apoptosis, led by cascade of molecular mechanism prior to both processes culminate into neurodegeneration. In present study, we urge to investigate the codon usage pattern of genes which are common before initiating autophagy and apoptosis. In the present study, we took up eleven genes (DAPK1, BECN1, PIK3C3 (VPS34), BCL2, MAPK8, BNIP3 L (NIX), PMAIP1, BAD, BID, BBC3, MCL1) that are part of molecular signaling mechanism prior to autophagy and apoptosis. We analyzed dinucleotide odds ratio, codon bias, usage, context, and rare codon analysis. CpC and GpG dinucleotides were abundant, with the dominance of G/C ending codons as preferred codons. Clustering analysis revealed that MAPK8 had a distinct codon usage pattern compared to other envisaged genes. Both positive and negative contexts were observed, and GAG-GAG followed by CTG-GCC was the most abundant codon pair. Of the six synonymous arginine codons, two codons CGT and CGA were the rarest. The information presented in the study may be used to manipulate the process of autophagy and apoptosis and to check the pathophysiology associated with their dysregulation. Show less

Zinc finger protein 1 (ZPR1), encoded by the ZNF259 gene, plays crucial roles in transcriptional regulation and cell cycle progression. Despite its known functions, its specific involvement in Metabolic Syndrome (MetS) remains debated. Genome-wide association studies have identified several genes, including ZNF259, implicated in lipid metabolism and associated with MetS. Single nucleotide polymorphisms (SNPs) in ZNF259 have been linked to altered lipid metabolism during the development of MetS. This study aims to investigate the association between MetS in Egyptian patients and three specific ZNF259 SNPs: rs964184, rs2075294, and rs2075290. The objective is to explore how these SNPs correlate with MetS development, other health outcomes, and their interaction with dyslipidemia biomarkers. 200 Egyptian participants were enrolled, and divided into two groups: 100 patients diagnosed with dyslipidemia and 100 healthy controls. The study involved comprehensive assessments, including lipid profile analysis, anthropometric measurements, and genotyping of rs964184, rs2075290, and rs2075294 in the ZNF259 gene using Real-Time Polymerase Chain Reaction (PCR). The findings indicate that rs964184 SNP correlates significantly with elevated plasma triacylglycerol (TG) levels, while rs2075290 and rs2075294 are associated with higher total serum cholesterol (TC) and TG levels. Among these SNPs, rs2075294 showed the highest predictive value (area under the curve of 0.748), followed by rs2075290 (0.738), and rs964184 (0.583), suggesting rs2075294 as the most influential SNP in MetS prediction. This study underscores the predictive role of ZNF259 SNPs in MetS risk among Egyptians. Future research should further explore the implications of ZNF259 in MetS pathogenesis and its potential as a biomarker for personalized health interventions. Show less

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance ( Show less

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families. Show less

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. Show less

Apolipoprotein A5 (APOA5) gene variants are associated with increased plasma triglycerides, a risk factor for metabolic syndrome (MS). The goal of the current study was the investigation of the distribution of T-1131C variant among obese adolescents with MS compared with healthy controls. The study included 150 obese adolescents (75 males and 75 females) with MS and 204 age and sex matched normal healthy controls (100 males and 104 females). The mean age of the patients was 15.47 ± 2.54 years, ranged from 17 to 20 years. They were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the mutation (T-1131C). The blood pressure, triglyceride and HOMA-R levels were significantly higher and HDL-C levels were significantly lower in carrier (TC+CC) compared to non-carrier (TT) MS patients. There was accumulation of -1131C allele frequency in the MS group (31.33% vs. control group 11.76%), p<0.001. The genotypes were in Hardy-Weinberg equilibrium both in the patients with metabolic syndrome and in the control subjects. Results of analysis of multiple regression models showed that the ApoA5 -1131C carriers showed an increased incidence of MS (OR=1.73, 95% CI: 1.41-2.11). The present study suggests that the 1131T>C polymorphism is a risk factor for the development of metabolic syndrome in obese adolescents. Show less