Genetic linkage analysis of 15 DFNB loci in a group of Iranian families with autosomal recessive hearing loss

Hearing loss [HL] is the most frequent sensory birth defect in humans. Autosomal recessive non-syndromic HL [ARNSHL] is the most common type of hereditary HL. It is extremely heterogeneous and over 70 loci [known as DFNB] have been identified. This study was launched to determine the relative contribution of more frequent loci in a cohort of ARNSHL families. Thirty-seven Iranian families including 36 ARNSHL families and 1 family with Pendred syndrome each with >/= 4 affected individuals, from seven provinces of Iran, were ascertained. DFNB1 contribution was initially studied by DNA sequencing of GJB2 and linkage analysis using the relative STR markers. The excluded families were then subjected to homozygosity mapping for fifteen ARNSHL loci. Sixteen families were found to be linked to seven different known loci, including DFNB1 [6 families], DFNB4 [3 families +1 family with Pendred syndrome], DFNB63 [2 families], DFNB2 [1 family], DFNB7/11 [1 family], DFNB9 [1 family] and DFNB21 [1 family]. DNA sequencing of the corresponding genes is in progress to identify the pathogenic mutations. The genetic causes were clarified in 43.2% of the studied families, giving an overview of the causes of ARNSHL in Iran. DFNB4 is ranked second after DFNB1 in the studied cohort. More genetic and epigenetic investigations will have to be done to reveal the causes in the remaining families

Molecular genetics, diagnosis and treatment of breast cancer: review article

Breast cancer is the most common cancer among women, and one out of 8 or 10 women is diagnosed with breast cancer. This type of cancer is an extremely heterogenous disease, which is classified into multiple categories including LCIS [Lobular carcinoma in situ], DCIS [Ductal carcinoma in situ], and invasive carcinoma. BRCA1 and BRCA2 are two major high-risk genes associated with hereditary breast cancer. Mutations in CHEK2 gene also contribute to a substantial fraction of familial breast cancer. Susceptibility alleles in other genes are also rare causes of breast cancer. More than 1000 mutations have been identified in BRCA1 and BRCA2, and molecular assays for detecting mutations in these genes are now well established. Mutations in BRCA1 and BRCA2 cause genomic instability, which leads to alterations in additional key genes including tumor suppressor genes and/or oncogenes

There is a promise of tailoring treatment programs for individual women in near future. The emergence of miRNAs as regulators of gene expression identifies them as a novel candidate for diagnostic and prognostic indicators and therapeutic targets. The ability of miRNAs to simultaneously regulates many target genes and makes them attractive candidates for regulating stem cell self-renewal and cell fate decisions. The involvement of miRNAs in the initiation and progression of human malignancy holds much potential for new developments in current diagnostic and therapeutic strategies in the management of patients with breast cancer. The identification of novel miRNAs, the elucidation of their mRNA targets, and an understanding of their functional effects will improve our knowledge of the roles of these novel biomarkers in carcinogenesis, including breast cancer, and open avenues for potential therapeutic intervention

[Mutation screening of GJB2 and GJB6 and genetic linkage study of three prevalent DFNB loci in Iranian families with autosomal recessive non-syndromic hearing loss]

The incidence of prelingual hearing loss [HL] is about 1 in 1000 neonates of which, more than 60% of cases are inherited. Non-syndromic HL [NSHL] is extremely heterogeneous: more than 100 loci have been identified. The most common form of NSHL is the autosomal recessive form [ARNSHL]. Here, we have investigated CX26 [GJB2] and CX30 [GJB6] gene mutation and linkage analysis of 3 known loci in Iranian families. A cohort of 36 big ARNSHL pedigrees from 7 provinces of Iran was investigated. All of the families were examined for the presence of GJB2 and GJB6 [del D13S1830 and del D13S1854] mutations using direct sequencing and multiplex PCR, respectively. The negative mutations pedigrees for the above-mentioned mutations, were then tested for the linkage to the 3 known loci, including DFNB3[MYO7A], DFNB4[SLC26A4] and DFNB7/11[TMC1], using STR markers and conventional PCR and PAGE. Six families had GJB2 mutations. No GJB6 mutation was found. Totally, 3 families showed linkage to DFNB4 and 1 family was linked to DFNB7/11. DFNB1 [GJB2] and DFNB4 are the main causes of ARNSHL in our study samples and GJB6 mutations are apparently absent in the Iranian population

Molecular basis of G6PD deficiency: Current status and its perspective

Glucose-6-phosphate dehydrogenase is an essential enzyme to cell growth. Its deficiency of enzyme plays an important role in senescence and death signaling. Also, it is actually the most common clinically important enzyme defect, not only in hematology, but also among all human known diseases. Clinical consequences of enzyme deficiency are: neonatal hyperbilirubinemia, acute hemolytic anemia, and chronic hemolytic anemia. The enzyme gene spans 18 kb on the X chromosome [xq28] and contains 13 exons. Its promoter is embedded in a CpG island that is conserved from mice to humans. The development of a number of PCR-based methods for the detection of known mutations in Glucose- 6-phosphate dehydrogenase has made it possible to detect enzyme deficiency and identify the specific mutation responsible with relative ease. We will discuss the mentioned clinical manifestations of glucose-6-phosphate dehydrogenase deficiency, Genetics, biochemistry and pathophysiology of the enzyme in details using newer published data and present most of the studies in Iranian population

Down's syndrome: cytogenetic studies in 150 case in Tehran

Cytogenetic studies were performed on 150 cases of Down's syndrome [DS] in lran. The standard trisomy 21 was found in 132 [88%] and translocation-trisomy 21 [+21] in 18 [12%] patients, i.e., t [21,21] in 1[0.63%] and mosaicism in 17[11.33%] cases. The comparison of the frequencies for mosaicism between different populations such as Denmark, Hungary, Egypt, Iraq, India, Australia and Iran demonstrated a difference in geographic distribution. There was a high incidence in the north of Europe towards Egypt and Iraq which decreased towards Iran and further towards the eastern region in the Indian ocean and India and further decreased towards Australia. Statistical analyses demonstrated significant differences between the data in Iran and Copenhagen, Hungary and Australia for mosaicism and translocation +21, and India, for translocation +21. The occurrence of translocation +21 decreased significantly from Denmark towards Egypt in Africa and Iraq in southwest Asia, then it increased from Iran towards Australia in the Pacific ocean.The comparison of cells having satellite associations [SA], significantly indicated the involvement of two and three SAs in DS cases. The study on the position of chromosomes in the metaphase plate, the occurrence of chromatid breaks and endoreduplication did not present any significance in DS cases

Molecular studies on the distribution of beta-thalassemia in Iran: the basis for prenatal diagnosis

By application of modern recombinant DNA technology, especially the polymerase chain reaction [PCR]/dot-blot hybridization techniques, we have investigated the molecular basis of Beta -thalassemia from four different regions of Iran: central, south-east, south and north. In this study, the DNA samples were isolated from patients and for the identification of the mutations, the 6 oligonucleotide probes for the mutations of IVS.l/nt. 110, IVS.l / nt.6, IVS. L / nt. l, nonsense codon 39, frameshift codon 8 and IVS.2/nt.l were selected with respect to their relative frequency in the neighbouring country, Turkey. Four mutations accounted for 76.2% and of these, the most frequent was the nonsense codon 39 mutation, which accounts for 60.3% of the Beta -thalassemia alleles tested. The remainder, in decreasing order of frequency,were frame shift cod on 8[9.5%],IVS.l/nt.6[4.8%]and IVS.l/nt.l 10[1.6%]. No hybridization was observed with the probes corresponding to the mutations of IVS.l/nt.l[G/A] and IVS.2/nt.l[G/A].These results also revealed that the distributions of different types of mutations were different in the four regions. This information and the introduction to the methodology used in this study will facilitate the prenatal diagnosis of the disease in Iran