Browsing by Author "Duman, Duygu"

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    Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss
    (2019) Duman, Duygu; Tıp Fakültesi
    We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.
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    Elucidating the genetic architecture of Adams–Oliver syndrome in a large European cohort
    (2018) Duman, Duygu; Tıp Fakültesi
    Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
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    Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability
    (2018) Duman, Duygu; Çelik, Pelin; Balcı, Özge; Sağlık Bilimleri Fakültesi
    The etiology of intellectual disability (ID) is heterogeneous including a variety of genetic and environmental causes. Historically, most research has not focused on autosomal recessive ID (ARID), which is a significant cause of ID, particularly in areas where parental consanguinity is common. Identification of genetic causes allows for precision diagnosis and improved genetic counseling. We performed whole exome sequencing to 21 Turkish families, seven multiplex and 14 simplex, with nonsyndromic ID. Based on the presence of multiple affected siblings born to unaffected parents and/or shared ancestry, we consider all families as ARID. We revealed the underlying causative variants in seven families in MCPH1 (c.427dupA, p.T143Nfs*5), WDR62 (c.3406C>T, p.R1136*), ASPM (c.5219_5225delGAG-GATA, p.R1740Tfs*7), RARS (c.1588A>G, p.T530A), CC2D1A (c.811delG, p.A271Pfs*30), TUSC3 (c.793C>T, p.Q265*) and ZNF335 (c.808C>T, p.R270C and c.3715C>A, p.Q1239K) previously linked with ARID. Besides ARID genes, in one family, affected male siblings were hemizygous for PQBP1 (c.459_462delAGAG, p.R153Sfs*41) and in one family the proband was female and heterozygous for X-chromosomal SLC9A6 (c.1631+1G>A) variant. Each of these variants, except for those in MCPH1 and PQBP1, have not been previously published. Additionally in one family, two affected children were homozygous for the c.377G>A (p.W126*) variant in the FAM183A, a gene not previously associated with ARID. No causative variants were found in the remaining 11 families. A wide variety of variants explain half of families with ARID. FAM183A is a promising novel candidate gene for ARID.
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    Otozomal resesif işitme kayıplı ailelerde otozigozite taraması ile MYO7A mutasyonlarının gösterilmesi
    (Biyoteknoloji Enstitüsü, 2011) Duman, Duygu; Akar, Nejat; Biyoteknoloji
    Hearing loss is the most common sensorial disorder. Congenital or prelingual hearing loss occurs approximately in one case per 1000 live births. Genetic causes account for 50% of cases. Additional findings are present in 30% of cases leading to the diagnosis of a syndrome . Autosomal recessive transmission occurs in 80% of hereditary deafness. To date, 38 genes in which mutations are responsible for autosomal recessive deafness have been identified. Mutations in GJB2, encoding connexin 26, are the most commonly identified cause of sensorineural hearing loss in Caucasians. Our data and the results of other studies show that the autosomal recessive inheritance accounts for more than 90% of genetic cases in Turkey. The GJB2 gene is the most common cause accounting for approximately 20% of cases.Due to the high rate of consanguineous marriages in Turkey as well as the traditional settlements in isolated small villages, rare autosomal recessive deafness alleles are frequently present in affected individuals . One of the previously identified deafness genes, MYO7A , is on the q13.5 region of chromosome 11. This gene consists of 48 coding exon, and codes a protein containing 2215 amino acids. Mutations in this gene cause Usher syndrome type 1B, atypical Usher syndrome, as well as non-syndromic recessive (DFNB2) and dominant (DFNA11) sensorineural hearing loss.This study included 55 unrelated multiplex families with sensorineural hearing loss. Autosomal recessive inheritance was evident with multiple siblings being affected as well as with the presence of parental consanguinity. The phenotypical and audiological characteristics of these families were evaluated and and no syndromic findings or environmental cause for hearing loss were detected. Mutations in GJB2 were negative in all families. Whenever genomewide SNP-based autozygozity mapping showed an autozygous segment flanking MYO7A in a family, mutation analysis was performed. The aim of this study was to reveal the spectrum of MYO7A mutations in Turkey to facilitate molecular diagnosis in clinical setting.MYO7A mutations were detected in 5 out of 7 families, where an autozygotic region demonstrated by microarrays was found to flank the gene. In the remaining two families no change has been identified in this gene.The following homozygous mutations were found in affected individuals : c.5824 G>A (p.G1924R) (one family), in c.5838delT (p.F1946LfsX24) (one family), c.6487 G>A (p.G2163S) (one family), c.5581 C>T (p.R1861X) (one family), c.5660 C>T (p.P1887L) (one family).This study shows that MYO7A mutations have a considerably high frequency in families with hearing loss in Turkey. Identifiying genes that cause hearing loss in Turkey will accelerate the molecular diagnosis and would improve accurate genetic counseling .