Splice-site variant in the RPS7 5'-UTR leads to a decrease in the mRNA level and development of Diamond-Blackfan...

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome.
• Pathogenic variants in ribosomal protein (RP) genes are common causes of DBA.
• Variants in 5'-untranslated regions (UTRs) are less understood and challenging to interpret.

Purpose of the Study:

• To investigate the functional consequences of a specific 5'-UTR splice-site variant (c.-19+1G>T) in the RPS7 gene.
• To determine the pathogenicity of this RPS7 variant in a family with DBA and myelodysplastic syndrome.

Main Methods:

• Trio whole exome sequencing was performed.
• Functional analysis using a luciferase expression system was employed.
• mRNA and protein expression levels were assessed.

Main Results:

• The RPS7 5'-UTR splice-site variant (c.-19+1G>T) was identified in affected individuals.
• Functional assays demonstrated that the variant disrupts splicing.
• A significant decrease in RPS7 mRNA and protein levels was observed.

Conclusions:

• The 5'-UTR splice-site variant c.-19+1G>T in the RPS7 gene is likely pathogenic.
• This finding contributes to understanding the genetic basis of Diamond-Blackfan anemia.
• The study highlights the importance of investigating UTR variants in genetic disorders.