Human TBX1 Missense Mutations Cause Gain of Function Resulting in the Same Phenotype as 22q11.2 Deletions
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TLDR
It is concluded that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss of function mutations or deletions.Abstract:
Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.read more
Citations
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β-Catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
Sung Ho Huh,David M. Ornitz +1 more
TL;DR: It is suggested that factors that affect Wnt—β-catenin signaling could modify the incidence and severity of DGS and reduce the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1.
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TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.
Tsutomu Ogata,Tetsuya Niihori,Noriko Tanaka,Masahiko Kawai,Takeshi Nagashima,Ryo Funayama,Keiko Nakayama,Shinichi Nakashima,Fumiko Kato,Maki Fukami,Yoko Aoki,Yoichi Matsubara +11 more
TL;DR: The results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders and imply thatTBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS-like phenotypes.
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Tbx1 is a negative modulator of Mef2c
Luna Simona Pane,Zhen Zhang,Rosa Ferrentino,Tuong Huynh,Luisa Cutillo,Antonio Baldini,Antonio Baldini +6 more
TL;DR: A microarray-based transcriptome analysis of E9.5 embryo tissues revealed a target of Tbx1 with critical developmental roles, so highlighting the power of the dosage gradient approach that was used.
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Tbx1 Genetically Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein Inhibitor Smad7 During Great Vessel Remodeling
TL;DR: It was shown that Smad7, an inhibitory Smad within the transforming growth factor-&bgr; pathway, is regulated by Tbx1, is required for arch artery remodeling, and genetically interacts with Tb x1 in this process, and acts upstream of Smad 7 controlling vascular smooth muscle and extracellular matrix investment of the fourth arch artery.
Journal ArticleDOI
Microduplications at 22q11.21 are associated with non-syndromic classic bladder exstrophy.
Markus Draaken,Heiko Reutter,Heiko Reutter,Charlotte Schramm,Enrika Bartels,Thomas M. Boemers,Anne-Karoline Ebert,Wolfgang Rösch,Annette Schröder,Raimund Stein,Susanne Moebus,Dietlinde Stienen,Per Hoffmann,Markus M. Nöthen,Michael Ludwig +14 more
TL;DR: These findings extend the phenotypic spectrum of the 22q11.2 duplication syndrome, and indicate that this aberration predisposes to CBE with incomplete penetrance.
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