title: A 3 base pair deletion in TBX1 leads to reduced protein expression and transcriptional activity.
abstract: Transcription factor TBX1 plays a pivotal role in heart development and has been implicated in 22q11.2 deletion syndrome. The structure of this protein has been elucidated, and several mutations have been identified that disrupt TBX1 localization, DNA/protein-binding, or mRNA expression. This study reports a mutation in the TBX1 gene that leads to significantly reduced expression of the mutant protein. A total of 773 conotruncal heart defect patients and 516 unrelated healthy control individuals were enrolled, none of which harbored a 22q11.2 deletion or duplication. We identified a mutation, c.303-305delGAA, located in the third exon of TBX1 that does not disrupt TBX1 mRNA expression or DNA binding activity, but results in decreased TBX1 protein levels and transcriptional activity. Through protein degradation studies we demonstrated that TBX1 is degraded primarily in proteasomes. Although the c.303-305delGAA mutation leads to low levels of the mutant protein, we found that increased protein degradation was not the cause, and we hypothesize that an alternate mechanism, such as translational inhibition, may be the cause.
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.|Scientific Research Center, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Shaohai
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Erge
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Pu
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Cao
authors.affiliation: Medical Laboratory, Shanghai Children's Medical Center, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pediatric Cardiology, Shanghai Children's Medical Center, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Sun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.|Department of Pediatric Cardiology, Shanghai Children's Medical Center, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Pediatric Cardiology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.|Scientific Research Center, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Rang
authors.initials: R
authors.lastname: Xu
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D059748:Proteolysis; D017384:Sequence Deletion; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D020825:T-Box Domain Proteins; C108625:TBX1 protein, human