Detection of novel mitochondrial mutations in cytochrome C oxidase subunit 1 (COX1) in patients with familial adenomatous polyposis (FAP)

Background: Familial Adenomatous Polyposis (FAP) is an Autosomal dominant inherited disorder and a rare form of colorectal cancer (CRC) that represents the most common gastrointestinal polyposis syndrome. Generally, cancers start to develop a decade after the appearance of the polyps. It manifests equally in both sexes, and incidence of this disease is in the second decade of life. Cytochrome c oxidase subunit I (COX1) is one of three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV. Alteration of the electron transport components by mutations in mtDNA may compromise the normal electron flow. This could lead to an increase of bifurcation and generation of super oxidase radicals and increase oxidative stress in various types of cancer cells.Methods: In this study, 21 Iranian patients and 20 healthy controls were investigated for presence of the mutations in mitochondrial coding gene (COXI) by PCR and sequencing analysis. FAP symptoms in our patients diagnosed by specialists from Khatamolanbia Hospital of Tehran, Iran. Then, the analysis of pathogenicity of the MT- COXI mutations was accomplished by the human mitochondrial genome database (Mitomap), PolyPhen, Sipred, Expacy and SIFT databases.Results: Our results showed that one patient has a heteroplasmic mutation which is located in MT- COXI gene, (C6041G) that cause change in amino acid (N → K) and according to the results of the in-silico analysis, it was assessed as pathogenic mutation. Also, this mutation is novel and has not previously been reported in any other disease. Furthermore, one homoplasmic variant (16362T>C) in COXI gene was also identified. The Bioinformatics’ predictions show that these mutations probably disturb the process of gene expression.Conclusion: This study is the most comprehensive study in the Iran and the results of this study can be used for genetic counseling and prenatal diagnosis and suggest that mutations in mitochondrial coding genes might lead to the production of defective proteins in the respiratory chains, so potentially lead to CRC in Iranian subjects. The prediction of the functional consequences of mutations, damaging effects and pathogenicity scores of missense and nonsense mutations performed by polymorphism phenotyping v2 (PolyPhen-2), scale-invariant feature transform (SIFT), I-Mutant online service and ENTPRISE-X. Finally to visualizing the 3D shapes and binding changes in the protein PyMol software was used.

کلیدواژه ها:

Familial adenomatous polyposis ، Mitochondria ، MT- COXI gene ، Mutations