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Identification and functional analysis of CITED2 mutations in patients with congenital heart defects
Silke Sperling1, Christina H Grimm, Ilona Dunkel
1Max Planck Institute for Molecular Genetics, Berlin, Germany. sperling@molgen.mpg.de
Abstract:
Recent reports have demonstrated that mice lacking the transcription factor Cited2 die in utero showing various cardiac malformations. We present for the first time functionally relevant mutations of CITED2 in patients with congenital heart defects (CHDs). CITED2 encodes a CREBBP/EP300 interacting transcriptional modulator of HIF1A and TFAP2. To study the potential impact of sequence variations in CITED2 for CHDs in humans, we screened a cohort of 392 well-characterized patients and 192 control individuals using DHPLC, sequencing, and Amplifluor genotyping techniques. We identified 15 CITED2 nucleotide alterations. Seven of these alterations were found only in CHD patients and were not detected in controls, including three mutations leading to alterations of the amino acid sequence (p.Ser170_Gly178del, p.Gly178_Ser179ins9, and p.Ser198_Gly199del). All three of these amino acid changing mutations cluster in the serine-glycine-rich junction of the protein, to which no functionality had heretofore been assigned. Here we show that these mutations significantly reduce the capacity of CITED2 to transrepress HIF1A, and that the p.Ser170_Gly178del mutation significantly diminishes TFAP2C coactivation. This reveals a modifying role for the serine-glycine-rich region in CITED2 function. In summary, the observation of these mutations in patients with septal defects indicates that CITED2 has a causative impact in the development of CHD in humans.
Insights
Mutations in the CITED2 gene are linked to congenital heart defects (CHDs) in humans. These genetic changes impair CITED2
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Mice lacking the Cited2 transcription factor exhibit in utero lethality with cardiac malformations.
- Congenital heart defects (CHDs) represent a significant global health concern with complex etiologies.
- CITED2 is a transcriptional modulator interacting with CREBBP/EP300, regulating HIF1A and TFAP2.
Purpose of the Study:
- To investigate the role of CITED2 gene variations in human congenital heart defects (CHDs).
- To identify and functionally characterize mutations in CITED2 associated with CHDs.
Main Methods:
- Screening of 392 CHD patients and 192 controls using DHPLC, sequencing, and Amplifluor genotyping.
- Identification and analysis of CITED2 nucleotide alterations.
- Functional assays to assess the impact of mutations on CITED2's transrepression of HIF1A and coactivation of TFAP2C.
Main Results:
- Fifteen CITED2 nucleotide alterations were identified, with seven exclusive to CHD patients.
- Three mutations altering the amino acid sequence (p.Ser170_Gly178del, p.Gly178_Ser179ins9, p.Ser198_Gly199del) were found in CHD patients.
- These mutations, located in the serine-glycine-rich region, significantly reduced CITED2's ability to transrepress HIF1A and diminished TFAP2C coactivation.
Conclusions:
- The serine-glycine-rich region of CITED2 plays a crucial role in its function.
- CITED2 mutations are implicated as a causative factor in the development of CHDs, particularly septal defects, in humans.
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