THYROGENE · Identification of new causative genes for congenital hypothyroidism

Identification of new causative genes for congenital hypothyroidism

Congenital hypothyroidism (CH) is the most common metabolic disorder in newborns and results invariably in mental retardation if untreated. The overall aim of the THYROGENE project was to identify genes causing CH. Identification of causative genes allows proper genetic counselling in families affected by the disease and opportunity to prevent recurrence of the disease in these families. Research objectives to achieve our aim were; to ascertain consanguineous families with CH; to determine mutations in known-causative disease genes; and to map new loci and identify novel causative genes for this disease. By establishing collaborations with key clinicians both in Turkey (TR) and the United Kingdom (UK), Dr Cangul brought together 250 CH cases all coming from consanguineous and/or multi-case families which represents the largest such cohort in the literature. Overall eight clinical centres from the TR and four from the UK contributed to the study. CH patients are clinically classified into two main groups: (i) dysgenesis cases in which there is a problem with the development of thyroid gland resulting in total absence of the gland (athyreosis), small gland (hypoplasia) or a mislocated gland (ectopy); (ii) dyshormonogenesis cases in which there is no problem with gland development but thyroid hormone synthesis has been compromised. In the first part of his project Dr Cangul focused on cases with dysgenesis and genetic loci causing congenital non-syndromic and non-goitrous CH (CHNG). There are four known genes causing CHNG phenotype; TSHR, PAX8, TSHB, and NKX2-5. Dr Cangul first carried out potential linkage analysis of all cases to these loci using microsatellite markers and then he performed mutation analysis of these genes by full direct sequencing. These analyses showed that TSHR was the main gene causing thyroid dysgenesis in his cohort and he identified several novel as well as previously reported mutations in this gene. He already published his findings in a journal article (Cangul et al. 2010a) and in a meeting proceedings (Cangul et al. 2010b), and presented in three international conferences. Lately he submitted another paper reporting for the first time in the literature that TSHR is the main cause of autosomal recessively inherited thyroid dysgenesis. Based on his results he developed a genetic testing strategy for definite diagnosis of autosomal recessive CH which will be a great help to clinicians practicing in this area. In the second part of his project Dr Cangul focused on cases with dyshormonogenesis and genetic loci causing this phenotype. There are seven known causative-genes for thyroid dyshormonogenesis (NIS, TPO, TG, DUOX2, DUOXA2, IYD, and PDS). Dr Cangul carried out potential linkage analysis of all cases to these loci using microsatellite markers and observed that TPO was the primary locus that most of dyshormonogenesis cases showed potential linkage to. Then he performed mutation analysis of this gene by full direct sequencing in all cases with potential linkage. He identified several novel and previously described TPO mutations. Dr Cangul is currently writing up the fourth paper out of this project reporting his findings on thyroid dyshormonogenesis which will provide further help for clinical diagnosis and classification of CH. In the second year of his project Dr Cangul also started genome-wide linkage analysis using high-resolution SNP array technology in samples which did not show potential linkage to any of 11 known CH loci. Simultaneously through a key collaboration he established with a research institute in Addenbrooke's Hospital in Cambridge, Dr Cangul sent out samples to prestigious Sanger Institute for whole exome sequencing (WES) which is the latest technological development in human molecular genetics. Combining the results of SNP array and WES he discovered two novel genes causing CH and currently working on validation studies on these two genes. These results will be a major contribution to CH research and lead to a prestigious publication in a high-impact journal. These discoveries will also provide new tools for clinical investigations towards aetiology of CH. In summary, Dr Cangul identified the main causes of CH in his large cohort and has already published some part of his findings in two papers. Recently he has submitted the revision of his third paper from this project and is currently writing up the forth one. He also represented his results in five national and international conferences. In addition by discovering novel causative genes for CH he has fulfilled all objectives set out in the proposal of this project. However validation and functional studies for novel genes will require further time and funding. Dr Cangul has secured further funding for these studies from Queen Elisabeth Hospital Birmingham Foundation Trust and currently working on these subjects. Impact The knowledge produced by this project is applicable to daily clinical practice and will help patients with CH and their larger families anywhere in the world. This knowledge will also help clinicians for the definite diagnosis and classification of the disease and provide additional info for prognosis and treatment options. Moreover, novel causative genes discovered in this project will provide new insights into thyroid physiology and molecular mechanisms involved in development of thyroid pathologies as well as new functional annotations to human genome, creating a link from bench to bed side with high potential for clinical and therapeutic applications. Therefore the results of this project might lead to the development of new protective and treatment strategies to improve medical care of thyroid pathologies, eventually contributing to European scientific excellence and competitiveness in the global race of biotechnology in finding new ways to treat human disease. Through this project Dr Cangul have acquired further competencies in human molecular genetics, mapping and sequencing as well as clinical research and networking. During this time he supervised 4 postgraduate students and gained experience in international project management which profoundly contributed to his professional maturity. This project provided Dr Cangul the opportunity to expand his expertise regarding the clinically relevant aspects of his research, which was a big step for his development towards an independent translational scientist. Now he aims to set up his own research group and conduct cutting edge research in the area of Medical Molecular Genetics to move European science forward. This project also helped to further strengthen the host institute as a centre of European excellence and set base for long-term future collaborations and grant applications.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз