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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Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.
Murim Choi,John Klingensmith +1 more
TL;DR: Chordin is a modifier for the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11DS.
Journal ArticleDOI
Atypical deletion of 22q11.2: detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays.
Marie-Paule Beaujard,Sandra Chantot,Michèle Dubois,Boris Keren,Wassila Carpentier,Philippe Mabboux,Sandra Whalen,Michel Vodovar,Jean-Pierre Siffroi,Marie-France Portnoï +9 more
TL;DR: It is concluded that FISH with the TBX1 probe is an accurate diagnostic tool for 22q11.2 DS, with a higher sensitivity than FISH using standard probes, detecting all but the rarest deletions, greatly reducing the false negative rate.
Journal ArticleDOI
Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders.
Janani Iyer,Santhosh Girirajan +1 more
TL;DR: It is clear that phenotypic assessment and complete genetic evaluation of large cohorts of individuals carrying specific CNVs and functional evaluation using multiple animal models are necessary to understand the molecular genetic basis of neurodevelopmental disorders.
Journal ArticleDOI
Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease
Akiko Yoshida,Hiroko Morisaki,Mai Nakaji,Masataka Kitano,Ki-Sung Kim,Koichi Sagawa,Shiro Ishikawa,Ichiro Satokata,Yoshihide Mitani,Hitoshi Kato,Kenji Hamaoka,Shigeyuki Echigo,Isao Shiraishi,Takayuki Morisaki +13 more
TL;DR: Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls, and a total of seven non-synonymous polymorphisms was found in the patients and controls.
Journal ArticleDOI
DiGeorge anomaly in the absence of chromosome 22q11.2 deletion.
TL;DR: These findings challenge a widely held belief that nearly 90% of DGA is due to chromosome 22q11.2 deletion.
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