Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder

• Published in: Genomics (San Diego, Calif.) Vol. 113; no. 4; pp. 1895 - 1905
• Main Authors: Panici, Brendan, Nakajima, Hosei, Carlston, Colleen M., Ozadam, Hakan, Cenik, Can, Cenik, Elif Sarinay
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021
• Subjects: Anemia, Diamond-Blackfan - genetics; Genes, Mitochondrial; Humans; Mutation; Rare Diseases - genetics; Ribosomal Proteins - genetics; RNA Splicing
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2021.04.020

Non-canonical intronic variants are a poorly characterized yet highly prevalent class of alterations associated with Mendelian disorders. Here, we report the first RNA expression and splicing analysis from a family whose members carry a non-canonical splice variant in an intron of RPL11 (c.396 +3A>G). This mutation is causative for Diamond Blackfan Anemia (DBA) in this family despite incomplete penetrance and variable expressivity. Our analyses revealed a complex pattern of disruptions with many novel junctions of RPL11. These include an RPL11 transcript that is translated with a late stop codon in the 3′ untranslated region (3'UTR) of the main isoform. We observed that RPL11 transcript abundance is comparable among carriers regardless of symptom severity. Interestingly, both the small and large ribosomal subunit transcripts were significantly overexpressed in individuals with a history of anemia in addition to congenital abnormalities. Finally, we discovered that coordinated expression between mitochondrial components and RPL11 was lost in all carriers, which may lead to variable expressivity. Overall, this study highlights the importance of RNA splicing and expression analyses in families for molecular characterization of Mendelian diseases. •RPL11 (c.396 + 3A > G) is a noncanonical splice variant that is causative for Diamond Blackfan Anemia (DBA)•RPL11 variant causes a complex pattern of splicing disruptions among carriers.•RPL11 transcript has similar abundance among carriers regardless of symptom severity.•Ribosomal subunit transcripts are overexpressed in individuals with congenital abnormalities and a history of anemia.•Coordinated expression between mitochondrial components and RPL11 is lost in all carriers.