Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin.
ABSTRACT CHEK2 encodes a serine/threonine-protein kinase which plays a critical role in DNA damage signaling pathways. CHEK2 directly phosphorylates and regulates the functions of p53 and BRCA1. Most women with breast and/or ovarian cancer are not carriers of mutant BRCA1 or BRCA2. Multiple studies have shown that a CHEK2*1100delC confers about a two-fold increased risk of breast cancer in unselected females and a tenfold increase in males. Moreover, studies have shown that first-degree relatives of bilateral breast cancer cases who carried the CHEK2*1100delC allele had an eight-fold increased risk of breast cancer. It has been suggested that CHEK2 functions as a low-penetrance susceptibility gene for cancers and multiplies the risks associated with other gene(s) to increase cancer risk. The main goal of this study was to evaluate and to compare the role of truncating mutations, splice junction mutations and rare missense substitutions in breast cancer susceptibility gene CHEK2. Present study was performed on 140 individuals including 70 breast cancer patients both with and without family history and 70 normal individuals. Written consent was obtained and 3 ml intravenous blood was drawn from all the subjects. DNA was extracted from all the samples through inorganic method published already. Primers were synthesized for all the 14 exons of CHEK2 gene. Coding and adjacent intronic sequences of CHEK2 gene were amplified and sequenced. Two genetic variants (p.H371Y, p.D438Y) were found in exon 10 and exon 11 of gene CHEK2 which were not found in any of the 70 control individuals from same geographical area and ethnic group. The genetic variant c.1312G>T (p.D438Y) identified in a patient with a family history of breast cancer. To our knowledge, this is first mutation scanning study of gene CHEK2 from Balochistan population.
Full-textDOI: · Available from: Abdul Hameed Baloch, Aug 03, 2014
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ABSTRACT: The TYR gene (MIM #6069333) is located at position 11q14.3 on the human chromosome, and encodes tyrosinase, which is expressed in melanocytes and controls the biosynthesis of melanin. Most TYR mutations eliminate the activity of tyrosinase, preventing melanocytes from producing any melanin throughout life. People with this form of albinism have white hair, light-coloured eyes and very pale skin. Some mutations in TYR reduce but do not completely eliminate tyrosinase activity, and allow some melanin to be produced. We report a Pakistani family with four members affected by oculocutaneous albinism (OCA). Blood samples were collected from all affected individuals, normal siblings and their parents. Genomic DNA was extracted, and sequence analysis of all the coding exons and adjacent intronic sequences of TYR was performed, which identified a novel missense substitution (p.Ile198Thr). Sequencing of TYR in 90 unrelated healthy individuals showed no sequence variant at this location. Our study expands the mutational spectrum of OCA1.Clinical and Experimental Dermatology 07/2014; 39(5):646-8. DOI:10.1111/ced.12382 · 1.23 Impact Factor