Familial hypercholesterolemia (FH), which is traditionally viewed as a monogenic disorder, has significant variability in its phenotypic expression, particularly its physical characteristics. Understa Show more
Familial hypercholesterolemia (FH), which is traditionally viewed as a monogenic disorder, has significant variability in its phenotypic expression, particularly its physical characteristics. Understanding the relationship between genotype and phenotype is essential for the effective diagnosis and management of this condition, especially in pediatric populations. This study aimed to investigate the correlation between genotype and phenotype in Egyptian children diagnosed with FH. A consecutive sample of 35 Egyptian children diagnosed with FH was recruited for the study. Phenotypic characteristics were comprehensively analyzed and correlated with genetic variants. Next-generation sequencing was employed to identify pathogenic variants in genes associated with FH. Among the 35 cases analyzed, 33 (94.3%) were found to have pathogenic variants in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or PCSK9 genes, with variants in LDLR accounting for approximately 90% of these cases. Zygosity analysis indicated that 63.6% of the children had biallelic pathogenic variants, with 42.4% being homozygous and 21.2% compound heterozygous, whereas the remaining 36.4% were heterozygous. The occurrence of xanthomas, early markers of atherosclerosis, abnormal echocardiographic findings, and elevated levels of total cholesterol and low-density lipoprotein cholesterol were significantly more common in children with homozygous FH. This study revealed a significant correlation between genotype and phenotype in Egyptian children with FH, with homozygous individuals experiencing more severe clinical symptoms. These findings underscore the importance of genetic screening in assessing disease severity and tailoring treatment strategies. Show less
NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, Show more
NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn's Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD. Show less