Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia

Abstract

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

“…The median age at presentation is 8 weeks, with a median age at diagnosis of 12 weeks. There have been cases of hydrops fetalis 6 , 7 . The male-to-female ratio of cases is approximately 1:1 despite rare cases of X-linked inheritance.…”

“…However, RPL5 gene mutations have been associated with cleft palate malformation and are the most important rate of malformations in DBA cases 16 , 17 , while RPL11 mutations are associated with the classic triphalangeal thumb 17 . Recently, mutations in the RPL15 gene have been identified in cases of hydrops fetalis in DBA patients 7 , and RPL35a gene mutations are associated with neutropenia.…”

Ribosome Biogenesis Alterations in Colorectal Cancer

“…RPL15 acts as a ribosomal assembly factor essential for the formation of the 60S subunit [145] and is also directly involved in pre-rRNA processing at the internal transcribed spacer 1 (ITS1) site of the 47S pre-rRNA [146,147]. RPL15 is significantly upregulated in LoVo, HCT-116, SW-480, and SW-620 CRC cell lines compared to non-transformed epithelial cells, and screening of the ONCOMINE 3.0 database (www.oncomine.org) indicated that RPL15 is overexpressed in CRC and associated with disease progression [148].…”

Fetal hydrops – a review and a clinical approach to identifying the cause

“…Fetal hydrops is a poor prognostic indicator and results from severe intrauterine anaemia. It is a rare manifestation of Diamond-Blackfan, with fewer than 10 cases reported [50]. Specific truncating mutations in the ribosomal protein RPL15 seem to confer the greatest risk of fetal hydrops [50].…”

“…It is a rare manifestation of Diamond-Blackfan, with fewer than 10 cases reported [50]. Specific truncating mutations in the ribosomal protein RPL15 seem to confer the greatest risk of fetal hydrops [50]. First line treatment is with glucocorticoids with chronic blood transfusions and stem-cell transplants reserved for glucocorticosteroid non-responders.…”