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The New Molecular Mechanism of Diamond-Blackfan Anemia Development is Described

Teamwork with Dmitry Rogachev National Medical Research Centre for Paediatric Haematology, Oncology and Immunology and the laboratory of functional genomics at RCMG was published in the journal Clinical Genetics (Q2, IF 4,296).

Diamond-Blackfan anemia (DBA) is a rare form of congenital erythrocytic aplasia characterized by a decrease in the number of erythroid progenitors in the bone marrow. The disease manifests itself in infancy as a severe macrocytic (less common normocytic) anemia, often accompanied by congenital abnormalities and malformations. About half of DBA cases are family-based, inherited by the autosomal dominant type with incomplete penetrance and varying expressiveness even within the same family.

The most common genetic cause of DBA is pathogenic variants in genes that encode ribosomal proteins. For example, about 25% of DBA patients were found to have pathogenic variants in the RPS19 gene. Also described the variants in the genes of erythroid transcription factor (GATA1), ribosome maturation factor (TSR2) and erythropoietin (EPO).

Staff of Dmitry Rogachev Centre performed exome sequencing of four family members, in which two sons were diagnosed with DBA. As a result, a variant of NM_001011.4:c.-19+1G was found in both sons, located at the donor site splicing the first non-coding exon of the RPS7 gene. This variant was also found in their father, whose death was caused by the development of myelodysplastic syndrome. As the variants of the 5'UTR genes of the ribosomal proteins are not well known, the pathogenicity of the variant remained questionable, but additional search of variants in DAB-associated genes have yielded no result.
To determine the pathogenicity of the variant, the functional analysis was carried out in vitro by the employees of the laboratory of functional genomics at RCMG with the use of minigenic constructions, expressing a part of the gene RPS7. The c.-19+1G variant has been shown to disrupt normal splicing of the first intron into the 5'UTR RPS7 gene, resulting in a significant decrease in mRNA and protein expression.

Thus, conclusive evidence of pathogenicity of variant NM_001011.4:c.-19+1G>T in gene RPS7 has been obtained.

The described molecular mechanism of pathogenicity was first identified in patients with DBA, allowing to broaden the range of pathogens underlying the disease.

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