title: Mutations in proteasome-related genes are associated with thyroid hemiagenesis.
abstract: OBJECTIVE
  Human thyroid development is a complex and still unexplained process. Thyroid hemiagenesis is a congenital anomaly, where one of the thyroid lobes fails to develop. In the majority of patients with thyroid hemiagenesis, the genetic background remains unknown. The aim of the study was to search for novel genetic contributors to the etiology of thyroid hemiagenesis.
  
  
  METHODS
  A cohort of 34 sporadic patients diagnosed with thyroid hemiagenesis and one three-generation family were subjected to comprehensive genomic examination. Initially, targeted screening of associated transcription factors, known to be linked to thyroid development, was performed. As a next step, genomic examinations were applied using high-resolution microarrays, whereas for the thyroid hemiagenesis family, additionally the whole exome sequencing was performed.
  
  
  RESULTS
  Screening of transcription factors revealed no causative mutations in the studied cohort. Genomic examinations revealed the presence of four recurrent defects (three deletions and one duplication) affecting highly conservative proteasome genes PSMA1, PSMA3, and PSMD3. In a thyroid hemiagenesis family a splice site mutation in a proteasome gene PSMD2 (c.612T > C cDNA.1170T > C, g.3271T > C) was found in both affected mother and daughter.
  
  
  CONCLUSIONS
  Our results shed a new light on etiology of thyroid hemiagenesis, so far suspected to be linked only to mutations in the genes directly involved in the thyroid development. We demonstrated, for the first time, that genomic alterations in proteasome-associated genes co-occur in patients presenting this developmental anomaly.
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Budny
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Szczepanek-Parulska
authors.affiliation: European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Science, Poznan, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zemojtel
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Szaflarski
authors.affiliation: Department of Human Molecular Genetics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rydzanicz
authors.affiliation: Laboratory of High Throughput Technologies, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wesoly
authors.affiliation: European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Science, Poznan, Poland.|Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Luiza
authors.initials: L
authors.lastname: Handschuh
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Kosma
authors.initials: K
authors.lastname: Wolinski
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piatek
authors.affiliation: Department of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Niedziela
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Ziemnicka
authors.affiliation: European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Science, Poznan, Poland.|Institute of Computing Science, Poznan University of Technology, Poznan, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Figlerowicz
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zabel
authors.affiliation: Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland. mruchala@ump.edu.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Ruchala
mesh_terms: D017353:Gene Deletion; D020440:Gene Duplication; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics*; D050033:Thyroid Dysgenesis / Q000235:genetics*
chemical_list: C101338:PSMD2 protein, human; D047992:TNF Receptor-Associated Factor 2; C000589188:PSMA1 protein, human; C488165:PSMA3 protein, human; D046988:Proteasome Endopeptidase Complex; C548045:proteasome activator PA700 subunit p58, human
keywords: Exome sequencing; Microarray; Proteasome; Thyroid hemiagenesis; Thyroid transcription factors