Browsing by Author "Boduroglu, Koray"

Now showing 1 - 4 of 4

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling
(OXFORD UNIV PRESS, 2013-01-01) Wieczorek, Dagmar; Boegershausen, Nina; Beleggia, Filippo; Steiner-Haldenstaett, Sabine; Pohl, Esther; Li, Yun; Milz, Esther; Martin, Marcel; Thiele, Holger; Altmueller, Janine; Alanay, Yasemin; Kayserili, Hulya; Klein-Hitpass, Ludger; Bohringer, Stefan; Wollstein, Andreas; Albrecht, Beate; Boduroglu, Koray; Caliebe, Almuth; Chrzanowska, Krystyna; Cogulu, Ozgur; Cristofoli, Francesca; Czeschik, Johanna Christina; Devriendt, Koenraad; Dotti, Maria Teresa; Elcioglu, Nursel; Gener, Blanca; Goecke, Timm O.; Krajewska-Walasek, Malgorzata; Guillen-Navarro, Encarnacion; Hayek, Joussef; Houge, Gunnar; Kilic, Esra; Simsek-Kiper, Pelin Ozlem; Lopez-Gonzalez, Vanesa; Kuechler, Alma; Lyonnet, Stanislas; Mari, Francesca; Marozza, Annabella; Dramard, Michele Mathieu; Mikat, Barbara; Morin, Gilles; Morice-Picard, Fanny; Ozkinay, Ferda; Rauch, Anita; Renieri, Alessandra; Tinschert, Sigrid; Utine, G. Eda; Vilain, Catheline; Vivarelli, Rossella; Zweier, Christiane; Nuernberg, Peter; Rahmann, Sven; Vermeesch, Joris; Luedecke, Hermann-Josef; Zeschnigk, Michael; Wollnik, Bernd
Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs{*}53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60\% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76\% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.
Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features
(BIOMED CENTRAL LTD, 2014-01-01) Arman, Ahmet; Bereket, Abdullah; Coker, Ajda; Kiper, Pelin Ozlem Simsek; Guran, Tulay; Ozkan, Behzat; Atay, Zeynep; Akcay, Teoman; Haliloglu, Belma; Boduroglu, Koray; Alanay, Yasemin; Turan, Serap
Background: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence
Clinical and Radiographic Features of the Autosomal Recessive form of Brachyolmia Caused by PAPSS2 Mutations
(WILEY, 2013-01-01) Iida, Aritoshi; Simsek-Kiper, Pelin Ozlem; Mizumoto, Shuji; Hoshino, Touma; Elcioglu, Nursel; Horemuzova, Eva; Geiberger, Stefan; Yesil, Gozde; Kayserili, Hulya; Utine, Gulen Eda; Boduroglu, Koray; Watanabe, Shigehiko; Ohashi, Hirofumi; Alanay, Yasemin; Sugahara, Kazuyuki; Nishimura, Gen; Ikegawa, Shiro
Brachyolmia is a heterogeneous skeletal dysplasia characterized by generalized platyspondyly without significant long-bone abnormalities. Based on the mode of inheritance and radiographic features, at least three types of brachyolmia have been postulated. We recently identified an autosomal recessive form of brachyolmia that is caused by loss-of-function mutations of PAPSS2, the gene encoding PAPS (3-phosphoadenosine 5-phosphosulfate) synthase 2. To understand brachyolmia caused by PAPSS2 mutations (PAPSS2-brachyolmia), we extended our PAPSS2 mutation analysis to 13 patients from 10 families and identified homozygous or compound heterozygous mutations in all. Nine different mutations were found: three splice donor-site mutations, three missense mutations, and three insertion or deletion mutations within coding regions. In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations. Phenotypic characteristics of PAPSS2-brachyolmia include short-trunk short stature, normal intelligence and facies, spinal deformity, and broad proximal interphalangeal joints. Radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates, broad ilia, metaphyseal changes of the proximal femur, including short femoral neck and striation, and dysplasia of the short tubular bones. PAPSS2-brachyolmia includes phenotypes of the conventional clinical concept of brachyolmia, the Hobaek and Toledo types, and is associated with abnormal androgen metabolism. (C) 2013 Wiley Periodicals, Inc.
RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome
(AMER SOC CLINICAL INVESTIGATION INC, 2015-01-01) Boegershausen, Nina; Tsai, I.-Chun; Pohl, Esther; Kiper, Pelin Ozlem Simsek; Beleggia, Filippo; Percin, E. Ferda; Keupp, Katharina; Matchan, Angela; Milz, Esther; Alanay, Yasemin; Kayserili, Hulya; Liu, Yicheng; Banka, Siddharth; Kranz, Andrea; Zenker, Martin; Wieczorek, Dagmar; Elcioglu, Nursel; Prontera, Paolo; Lyonnet, Stanislas; Meitinger, Thomas; Stewart, A. Francis; Donnai, Dian; Strom, Tim M.; Boduroglu, Koray; Yigit, Goekhan; Li, Yun; Katsanis, Nicholas; Wollnik, Bernd
The genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.