ABSTRACT
Melanocortin 4 receptor (MC4R) mutations are the commonest cause of monogenic obesity through dysregulation of neuronal pathways in the hypothalamus and prefrontal cortex that regulate hunger and satiety. MC4R also regulates neuropathic pain pathways via JNK signaling after nerve injury. We show evidence of corneal small fiber degeneration in 2 siblings carrying a heterozygous missense variant c.508A>G, p.Ille170Val in the MC4R gene. Both children were treated with once weekly semaglutide for 6 months with no change in weight, and only a minor improvement in HbA1c and lipid profile. However, there was evidence of nerve regeneration with an increase in corneal nerve fiber density (CNFD) [child A (13.9%), child B (14.7%)], corneal nerve branch density (CNBD) [child A (110.2%), child B (58.7%)] and corneal nerve fiber length (CNFL) [child A (21.5%), child B (44.0%)].
Subject(s)
Nerve Regeneration , Receptor, Melanocortin, Type 4 , Humans , Receptor, Melanocortin, Type 4/genetics , Male , Female , Child , Nerve Regeneration/drug effects , Glucagon-Like Peptides/therapeutic use , Glucagon-Like Peptides/pharmacology , Nerve Fibers/drug effects , Nerve Fibers/pathology , Mutation , Obesity/drug therapy , Obesity/genetics , Cornea/drug effects , Cornea/innervation , Cornea/pathology , Pediatric Obesity/drug therapy , AdolescentABSTRACT
In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of ß-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through ß-catenin/Akt/mTOR signaling pathways.
ABSTRACT
The leptin-melanocortin pathway is pivotal in appetite and energy homeostasis. Pathogenic variants in genes involved in this pathway lead to severe early-onset monogenic obesity (MO). The MC4R gene plays a central role in leptin-melanocortin signaling, and heterozygous variants in this gene are the most common cause of MO. A targeted gene panel consisting of 52 obesity-related genes was used to screen for variants associated with obesity. Variants were analyzed and filtered to identify potential disease-causing activity and validated using Sanger sequencing. We identified two novel heterozygous variants, c.253A>G p.Ser85Gly and c.802T>C p.Tyr268His, in the MC4R gene in two unrelated patients with morbid obesity and evaluated the functional impact of these variants. The impact of the variants on the MC4R gene was assessed using in silico prediction tools and molecular dynamics simulation. To further study the pathogenicity of the identified variants, GT1-7 cells were transfected with plasmid DNA encoding either wild-type or mutant MC4R variants. The effects of allelic variations in the MC4R gene on cAMP synthesis, MC4R protein level, and activation of PKA, ERB, and CREB signaling pathways in both stimulated and unstimulated É-MSH paradigms were determined for their functional implications. In silico analysis suggested that the variants destabilized the MC4R structure and affected the overall dynamics of the MC4R protein, possibly leading to intracellular receptor retention. In vitro analysis of the functional impact of these variants showed a significant reduction in cell surface receptor expression and impaired extracellular ligand binding activity, leading to reduced cAMP production. Our analysis shows that the variants do not affect total protein expression; however, they are predicted to affect the post-translational localization of the MC4R protein to the cell surface and impair downstream signaling cascades such as PKA, ERK, and CREB signaling pathways. This finding might help our patients to benefit from the novel therapeutic advances for monogenic forms of obesity.
Subject(s)
Leptin , Obesity, Morbid , Humans , Leptin/genetics , Obesity, Morbid/genetics , Qatar , Alleles , alpha-MSH/pharmacology , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , MutationABSTRACT
CONTEXT: Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of severe early-onset obesity. Mutations in the genes encoding the MC4R, leptin, and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity. OBJECTIVE: To unravel the genetic causes of early-onset obesity in the population of Qatar. METHODS: In total, 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes. RESULTS: Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, 7 variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C>T p.T162I variant was the most frequent MC4R variant seen in 5 patients. CONCLUSION: We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East and revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.
Subject(s)
Leptin , Obesity , Humans , Child , Leptin/genetics , Qatar/epidemiology , Obesity/epidemiology , Obesity/genetics , Obesity/pathology , Mutation , Phenotype , Receptor, Melanocortin, Type 4/genetics , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
Introduction: Premature ovarian insufficiency (POI) is a primary cause of infertility with variable clinical manifestations. POI is a multifactorial disease with both environmental and known genetic etiologies, but data on the genetic variations associated with POI in the Middle East and North Africa (MENA) region are scarce. The aim of this study was to systematically review all known genetic causes of POI in the MENA region. Methods: The PubMed, Science Direct, ProQuest, and Embase databases were searched from inception to December 2022 for all reports of genetic variants associated with POI in the MENA region. Clinical and genetic data were collected from eligible articles, and ClinVar and PubMed (dbSNP) were searched for variants. Results: Of 1,803 studies, 25 met the inclusion criteria. Fifteen studies were case-control studies and ten were case reports representing 1,080 non-syndromic POI patients in total. Seventy-nine variants in 25 genes associated with POI were reported in ten MENA countries. Of the 79 variants, 46 were rare and 33 were common variants. Of the 46 rare variants, 19 were pathogenic or likely pathogenic according to ACMG classification guidelines and ClinVar. No clear phenotype-genotype association was observed. Male family members carrying pathogenic variants also had infertility problems. Discussion: To our best knowledge, this is the first systematic review of the genetic variants associated with POI in the MENA region. Further functional studies are needed to assess the disease-causing molecular mechanisms of these variants. Knowledge of the genetic basis of POI in the Middle East could facilitate early detection of the condition and thus early implementation of therapeutic interventions, paving the way for precision medicine options in specific populations.