Abstract
Obesity is multifactorial disease with a high heritability, in which monogenic forms although uncommon provide very important information on energy homoeostasis pathways. Such monogenic forms may increase in consanguineous population such as that in Pakistan. The purpose of this study was to examine the role of pathogenic variants of two important genes of the leptin- melanocortin pathway, namely “Melanocortin-4 Receptor (MC4R) and Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK-1) in severe obesity among Pakistani adults.
We performed a candidate gene screening in a well phenotyped cohort of ten unrelated Pakistani patients with severe obesity (Body Mass Index ≥ 30kg/m2). The genomic DNA was isolated from the peripheral blood and targeted exons of MC4R and PCSK-1 were amplified using polymerase chain reaction (PCR) and bidirectional Sanger Sequencing. To identify the sequence variants, alignment with reference genome and validation with against public databases (dbSNP,ClinVar, gnomAD, COSMIC) was performed.
Interestingly, no pathogenic or probably pathogenic mutations were found on the PCSK-1 gene. The sequencing of MC4R gene on the other hand identified putative disease associated variants in 4 out of 10 subjects (40%). These were two frameshift deletions (one novel, c.498delC and one known pathogenic, c.431delT) and one missense variant (c.772T>G; p.Trp258Gly) in COSMIC and one synonymous variant (c.717C>G).
Our results show MC4R as the key determining factor of severe obesity in current Pakistani cohort, which its consistent contribution in appetite regulation. The lack of PCSK-1 variant indicate that it could be less chronic monogenic factor in this particular cohort. The study highlights the paramount role of genetic screening of MC4R in the clinical assessment of extreme obesity in consanguineous groups. It provides the basis of correct diagnosis, genetic counseling and provides the door to individualized treatment plans with specific therapies to correct malfunctioning melanocortin pathways becoming accessible.