Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions
Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions
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DOI：
10.1086/511993
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发表时间：
2007-03-01
影响因子：
9.8
通讯作者：
Rauch, Anita
中科院分区：
文献类型：
--
作者：
Zweier, Christiane;Sticht, Heinrich;Rauch, Anita
缺失22q11.2综合征是已知最常见的微缺失综合征，与高度可变的表型相关，包括digegeorge综合征和Shprintzen综合征。虽然T-box转录因子基因TBX1的单倍性不足被认为是导致该表型的原因，但迄今为止，只有TBX1的四种不同的点突变被报道与22q11.2缺失综合征的六个主要特征相关。虽然，对于两个截断突变，功能丧失先前已被证明，错义突变的病理机制仍然未知。我们报告了一个新的杂合错义突变，H194Q，在家族病例的Shprintzen综合征，并表明这和两个先前报道的错义突变导致功能的获得，可能是通过稳定蛋白质二聚体DNA复合物。因此，我们得出结论，TBX1功能获得突变可能导致与功能丧失突变或缺失引起的单倍不全相同的表型谱。
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.