Two novel C-terminal frameshift mutations in the β-globin gene lead to rapid mRNA decay

BMC Medical Genetics

Research Article

Urszula Demkow¹  Anna Adamowicz-Salach²  Anna Klukowska²  Katarzyna Rawa³  Pawel Szczesny³  Beata Burzynska³  Danuta Plochocka³  Monika Gora³  Roman J. Szczesny⁴  Andrzej Dziembowski⁴  Ewelina P. Owczarek⁴ 

[1] Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, 02-091, Warsaw, Poland;Department of Paediatrics, Haematology and Oncology, Medical University of Warsaw, 02-091, Warsaw, Poland;Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warszawa, Poland;Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warszawa, Poland;Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland;

关键词: β- thalassemia;    Frameshift mutations;    Gene expression;    mRNA degradation;   

DOI  :  10.1186/s12881-017-0428-1

 received in 2016-10-17, accepted in 2017-05-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe thalassemia syndromes are classified according to the globin chain or chains whose production is affected. β-thalassemias are caused by point mutations or, more rarely, deletions or insertions of a few nucleotides in the β-globin gene or its immediate flanking sequences. These mutations interfere with the gene function either at the transcriptional, translational or posttranslational level.MethodsTwo cases of Polish patients with hereditary hemolytic anemia suspected of thalassemia were studied. DNA sequencing and mRNA quantification were performed. Stable human cell lines which express wild-type HBB and mutated versions were used to verify that detected mutation are responsible for mRNA degradation.ResultsWe identified two different frameshift mutations positioned in the third exon of HBB. Both patients harboring these mutations present the clinical phenotype of thalassemia intermedia and showed dominant pattern of inheritance. In both cases the mutations do not generate premature stop codon. Instead, slightly longer protein with unnatural C-terminus could be produced. Interestingly, although detected mutations are not expected to induce NMD, the mutant version of mRNA is not detectable. Restoring of the open reading frame brought back the RNA to that of the wild-type level.ConclusionOur results show that a lack of natural stop codon due to the frameshift in exon 3 of β-globin gene causes rapid degradation of its mRNA and indicate existence of novel surveillance pathway.

【 授权许可】

CC BY   
© The Author(s). 2017