Functional role of transcriptional factor TBX5 in pre-mRNA splicing and Holt-Oram syndrome via association with SC35.

[holt-oram syndrome]

TBX 5 is a T -box transcriptional factor required for cardiogenesis and limb development . TBX 5 mutations cause Holt-Oram syndrome characterized by congenital heart defects and upper limb deformations . Here we establish a novel function for TBX 5 in pre-m RNA splicing , and we show that this function is relevant to the pathogenesis of Holt-Oram syndrome , providing a novel pathogenic mechanism for the disease . Proteomics in combination with affinity purification identifies splicing factor SC 35 as a candidate TBX 5 -associating protein . Co -immunoprecipitation and glutathione S-transferase pulldown assays confirm the complex formation between TBX 5 and SC 35 . TBX 5 can bind to RNA homopolymers (polyribonucleotides ) and to the 5 '-splice site , which overrides the binding of SC 35 to the same RNA . Overexpression of TBX 5 increases the efficiency of pre-m RNA splicing and regulates alternative splice site selection . However , co -expression of TBX 5 and SC 35 antagonizes each other 's positive effect on splicing . The most severe TBX 5 mutation , G 8 0 R , with complete penetrance of the cardiac phenotype , strongly affects pre-m RNA splicing , whereas other mutations with incomplete penetrance of the cardiac phenotype , including R 237 Q , do not alter the splicing activity of TBX 5 . This study establishes TBX 5 as the first cardiac gene and the first human disease gene with dual roles in both transcriptional activation and pre-m RNA splicing .

Diseases
Validation

Diseases presenting "limb development" symptom

achondroplasia

holt-oram syndrome

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