Browsing by Author "Tekin, Mustafa"
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Item ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families(Informa Healthcare, 2013-10) Subaşıoğlu Uzak, Aslı; Çakar, Nilgün; Çomak, Elif; Yalçınkaya, Fatoş; Tekin, Mustafa; https://orcid.org/0000-0002-1853-0101; Tıp FakültesiDistal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C4T (p.R31X), c. 232G4A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype–phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling.Item ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families.(Taylor & Francis, 2013-10-01) Subaşıoğlu Uzak, Aslı; Çakar, Nilgün; Çomak, Elif; Yalçınkaya, Fatoş; Tekin, Mustafa; Tıp FakültesiDistal renal tubular acidosis (DRTA) is characterized by tubular defects in urinary acidification and hyperchloremic metabolic acidosis, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis and nephrolithiasis. Mutations in ATP6V1B1 cause DRTA associated with sensorineural hearing loss. The objective of this multicenter study is to screen DRTA patients with sensorineural hearing loss for ATP6V1B1 gene mutations and present genotype/phenotype correlation. Clinical data in five unrelated consanguineous families with DRTA and hearing loss were obtained in Turkey. For mutation screening, all coding exons of ATP6V1B1 were PCR-amplified and sequenced from genomic DNA. In our cohort of five families, there were four different homozygous ATP6V1B1 mutations in affected individuals: c.91C>T (p.R31X), c.232G>A (p.G78R), c.497delC (p.T166RfsX9) and c.1155dupC (p.I386HfsX56). Our study shows that rare and family-specific variants in ATP6V1B1 are responsible for DRTA and sensorineural hearing loss syndrome in Turkey. While firm genotype–phenotype correlations are not available, detailed clinical and molecular analyses provide data to be used in genetic counseling.Item Bir grup Türk hastada SLC26A4 gen analizi(Sağlık Bilimleri Enstitüsü, 2005) Duman, Duygu Akçayöz; Tekin, Mustafa; Çocuk Sağlığı ve HastalıklarıGene Analysis in a Group of Turkish PatientsCongenital or prelingual onset hearing loss affects 1 in 1000 newborns, half of which isconsidered to be caused by genetic factors. Mutations in a number of genes manifestingthemselves with autosomal recessive inheritance are believed to be responsible inapproximately 80% of genetic cases. About 30 % of the hereditary hearing loss also haveother clinical signs associated with deafness. Pendred syndrome , initially described asdeafness and goiter, has been reported as the most common form of syndromic hearing loss.Mutations in the SLC26A4 gene, encoding for a chloride-iodide transporter protein, pendrin,are responsible for the syndrome. Although four different mutations in SLC26A4 were foundin two Turkish families, a systematic search for the frequency of this syndrome or mutationanalysis in the Turkish population has not been reported previously. In this study we aimed todetermine the frequency of probands with deafness and goiter among Turkish people withhearing loss, and also to screen for SLC26A4 mutations in cases with Pendred syndrome. Asa consequence of our results we hoped to provide better genetic counselling to ourpopulation with hearing loss.A total of 333 probands with pre-lingual-onset severe to profound sensorineural hearing losscoming from reportedly unrelated 293 families, were included in the study after exclusion ofcases where unequivocal evidence was present for an environmental etiology. All patientswere found to be negative for GJB2 and mitochondrial A1555G mutations. Goiter was notedin 11 probands (3.3%) coming from eight unrelated families (3%). None of these studentshad been diagnosed with Pendred syndrome before. Genomic DNA was extracted by aconventional phenol- chloroform method. The SLC26A4 gene was screened with PCR-SSCPprotocols. Samples showing band changes were sequenced on an automated DNAsequencer.Mutation analyzes revealed three different mutations, c.2168A>G (p.His723Arg), c.716T>A(p.Val239Asp) and c.1341delG in homozygous state in probands coming from three familieswith more than one affected member.The prevalence of goiter in the Turkish children from the school of deaf is 2.8 %. In thisstudy following the mutation anaysis Pendred syndrome was definitively diagnosed in five outof 333 (1.5%) probands or in other words in three out of 293 independent families (1%) inTurkey. Our results and those of two previous reports suggest that the mutational spectrumof Pendred syndrome in the Turkish population is heterogeneous and private mutations areresponsible for the disorder in unrelatedl families. Therefore, screening of the whole gene isrecommended in Turkish families with Pendred syndrome originating from Turkey.Key words: Goiter, Hearing loss, Pendred syndrome, SLC26A4, Turkish population.Item Güneydoğu Anadolu'daki işitme engellilerde GJB2 mutasyonlarının sıklığı(Biyoteknoloji Enstitüsü, 2008) Taylan, Doruk; Tekin, Mustafa; BiyoteknolojiPrelingual deafness occurs with a frequency of approximately 1 in 1000 children. More than 50% of prelingual deafness is caused by genetic factors in developed countries, while remaining is environmentally caused.Affected individuals who are classified certainly of the genetic cases are divided into syndromic and non-syndromic forms. 70% of these cases with genetic origin are referred to as having the non-syndromic form because of absent additional findings. The most common form of hereditary hearing loss is transmitted with autosomal recessive inheritance. Non-syndromic hearing loss may be familial or sporadic. Mutations in GJB2 have been identified among the deaf living in many countries, 35delG being the most common mutation in Caucasoid populations. The GJB2 gene is mapped to the DFNB1 locus at chromosome 13q12, is the main gene for prelingual hearing loss.Previous studies completed in Turkey have determined that the mutation frequency of GJB2 in the deaf population varies from region to region. In those studies, the number of included families from Southeast Anatolia was not sufficient. In this study, unrelated 45 probands, who originated from Southeast Anatolia, with non-syndromic congenital or prelingual onset sensorineural hearing loss have been studied. Mutations in the coding and not coding exons of the GJB2 gene were screened with PCR-RFLP, PCR-SSCP and DNA sequencing methods. Biallelic GJB2 mutations were detected in seven families (7/45=15.5% ; 95% confidence interval of 5% to 26%).Our results show that GJB2 mutations are an important cause of the hearing loss in Southeast Anatolia. However, they are relatively less common compared to those observed in other parts of Anatolia.Item İşitme Kaybının Genetik ÖzellikleriTekin, MustafaItem PTPN11 gen mutasyonlarının noonan sendromlu hastalarda taranması(Biyoteknoloji Enstitüsü, 2006) Cengiz, Filiz Başak; Tekin, Mustafa; BiyoteknolojiNoonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial features, short stature, congenital heart disease, cryptorchidism, and lymphatic dysplasia. This syndrome is estimated to be seen in 1/1500-1/2500 live births. Mutations in the PTPN11 gene are detected in nearly 50% of affected individuals. The PTPN11 gene encodes for a nonreceptor protein tyrosine phosphatase, SHP-2, which contains N-SH2 and C-SH2 domains in the amino terminal and a PTP domain in the carboxy terminal. PTPN11 missense mutations cluster in the N-SH2 and PTP domains, which are involved in switching the protein between its inactive and active conformations. In this study, 20 patients, clinically diagnosed with NS, were screened for mutations in 8 exons of the PTPN11 gene. These exons were screened with PCR-SSCP, PCR-DHPLC, and PCR-DNA sequence analysis protocols. Mutation analysis revealed the p.Asn308Asp alteration in three patients in exon 8, p.Ala72Ser alteration in a patient in exon 3, p.Tyr63Cys alteration in a patient in exon3, and p.Asn58Asp alteration in a patient in exon 3. All mutations were detected with DHPLC. However, only p.Tyr63Cys and p.Ala72Ser mutations were found with SSCP. The p.Asn308Asp mutation was confirmed with a PCR-RFLP protocol. Our results show that it will be practical to first screen exons 3 and 8 of PTPN11 with PCRDHPLC in patients with NS. Key Words: DHPLC, DNA sequence analysis, Noonan syndrome, PTPN11, PCR, SSCPItem Sendromik olmayan otozomal resesif işitme kaybı ile ilgili yeni genlerin ortaya çıkarılması(Biyoteknoloji Enstitüsü, 2008) Aslan, İdil; Tekin, Mustafa; BiyoteknolojiHearing loss is the most common sensoineural disorder. Congenital or prelingualhearing loss occurs approximately in one case per 1000 live births. Genetic causesaccount for 50%of cases. Additional findings are present in 30%of cases, which arereferred to as having syndromic deafness. Autosomal recessive transmission occursin 80%of hereditary deafness. To date, 27 genes, in which mutations are responsiblefor autosomal recessive deafness have been identified.We aimed to identify novel genes for non-syndromic autosomal recessive deafnessby searching four candidate genes (TMHS, TRPA1, GJA7, SLC12A2) in deaffamilies.Ninety-seven families with parental consanguinity segregating autosomal recessiveprofound prelingual deafness were included in this study. Mutations in GJB2 werescreened and found to be negative in all families. Homozygous run flanking the fourstudied genes were evaluated with microsatellite and single nucleoted polymorphism(SNP) genotyping in 66 and 51 families respectively.Microstellite followed by SSCP and no change was found in TMHS gene.Ahomozygous p.Arg3Cys (c.7C>T) change was found in TRPA1 gene. However it wasassensed to be a polymorphism based on previously reported studies.Heterozygous p.Asp297Asn (c.889G>A) was detected in GJA7 gene in two unrelatedfamilies. Although this change has not been reported earlier, it was considered to be apolymorphism because this position is not conserved in different species and theamino acid change was not assensed to be not significant for the alteration of proteinfunction.No DNA sequence change was found in the SLC12A2 gene.In conclusion TMHS, TRPA1, GJA7 and SLC12A2 genes are not a common cause ofautosomal recessive sensorineural hearing lossItem Sendromik olmayan otozomal resesif işitme kaybı olan beş ailede genom boyunca genotipleme analizi(Biyoteknoloji Enstitüsü, 2008) Sırmacı, Aslı; Tekin, Mustafa; BiyoteknolojiCongenital or prelingual hearing loss occurs approximately in one case per 1000 live births. Genetic causes are responsible in 50% of cases. Additional findings are present in 30% of cases, which are referred to as having syndromic deafness. Autosomal recessive transmission occurs in 80% of hereditary deafness. To date, 27 genes, in which mutations are responsible for autosomal recessive deafness have been identified. Five families with parental consanguinity segregating autosomal recessive deafness, which have at least 3 affected individuals by profound prelingual deafness were included in this study. These families were ascertained among a larger number of families with initial findings suggesting the presence of a causative DNA change in a known deafness gene. Mutations in GJB2 were screened and found to be negative. Genomic DNA extracted by using standard phenol-chloroform method was used to genotype genomewide SNPs with microarray. Homozygous blocks flanking a known deafness gene in affected family members were considered to be evidence for the presence of a causative change in a given deafness gene. All family members were later included for microsatellite marker genotyping to determine co-segregation with the phenotype.Initial screening with genomewide SNPs suggested the presence of responsible changes in genes CDH23 (1 family), TMIE (1 family), and TMC1 (3 families). CDH23, encodes calcium dependent cell-cell adhesion glycoproteins, which is expressed in the neurosensory epithelium. The protein is thought to be involved in stereocilia organization and hair bundle formation. TMC1 encodes an ion-transport protein. The specific function of this gene is unknown but as demonstrated in the mouse, Tmc1 mRNA is expressed in hair cells of the postnatal cochlea and vestibular organs and is required for normal function of cochlear hair cells. The specific function of TMIE is unknown but Tmie is required for normal postnatal maturation of sensory hair cells in the cochlea. Mutations were screened using PCR- SSCP methods for TMC1 and CDH23 genes followed by direct sequencing. Direct DNA sequencing was performed for the TMIE gene. A missense mutation, c.1333C>T (p.R445C), was found in one family and a splice side mutation, IVS6+2 T>A, was identified in the another. In the third family, a deletion was identified which includes exons 19 and 24. In the CDH23 gene, an intronic c.3595-13C>T change was found. None of these mutations has been previously reported. The c.250C>T (p.R84W) mutation was detected in the TMIE gene in one family. This mutation has been previously described.In our study we identified causative DNA changes in five families segregating nonsyndromic autosomal recessive deafness.Item The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?(2016) Tekin, Mustafa; Tıp FakültesiThe vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657de15; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657de15 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657de15 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657de15 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657de15 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657de15 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.Item Türk toplumunda GJB2 (gap junction beta 2 geni; connexin 26) mutasyonları(Sağlık Bilimleri Enstitüsü, 2004) Boğoçlu, Gönül; Tekin, Mustafa; Çocuk Sağlığı ve HastalıklarıGJB2 (Gap Junction Beta 2 Gene; Connexin 26) Mutations in the Turkish Population Hearing loss occurs in approximately 1 to 3 of 1000 children and approximately 50% of cases have genetic origin. Affected individuals with no additional findings are referred to as nonsyndromic cases. Of these cases with genetic origin, 70% are nonsyndromic. The most common form of hereditary hearing loss is autosomal recessive nonsyndromic hearing loss. Nonsyndromic hearing loss can be diagnosed in persons coming from multiplex or simplex families. Mutations in GJB2 have been identified in deaf people living in many countries, 35delG being the most common mutation in Caucasoid populations. Although in the etiology of hearing loss are a variety of factors, mutations in one gene, GJB2, which encodes for the protein Connexin 26, account for up to 50% of cases of nonsyndromic sensorineural hearing loss in some populations. Here, we present our data about the genetic causes of cases with hearing loss in the Turkish population. Our study group included 358 probands with nonsyndromic hearing loss, in which the age range was between 2-33 years. Of these, 190 cases were multiplex and 168 were simplex. We found 51 probands (14,2%) in homozygous state and 26 probands (7,3%) in heterozygous state for the 35delG mutation. 281 probands (78,5%) were found to be negative for this mutation. Moreover, 10 probands were found to carry the W24X, T55N, 167delT, 299-300delAT, 333-334delAA, 236_239delTGCAinsAGATCCG, delE120, R143W and Y155X mutations as a compound heterozygous mutation with 35delG. 16 probands were found to carry no mutations in the GJB2 coding region. In multiplex cases, mutation screening was performed by PCR-SSCP techniques and probands having band differentiation were analysed using DNA sequencing. As a result, the V27I, El 14G polymorphisms and the delE120 mutation were observed. In our population, mutations in GJB2 present a pattern similar to the distribution of the GJB2 mutations in different countries of Europe. Showing historical relationship with Eastern Asia, polymorphisms belonging to Asian populations were found to be prevalent in our population. The discovery of mutations in GJB2 for the cause of congenital hearing loss will be useful for the early diagnosis and intervention of hearing loss. Key Words: Connexin 26, gap junction, GJB2 gene, hearing loss, Turkish population, 35 delG mutation.