@article{dd207dbba01d4815a5c3a95ff342174e,
title = "Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome",
abstract = "Shwachman-Diamond syndrome (SDS; OMIM #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present 3 unrelated Korean SDS patients who carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow–specific somatic uniparental disomy in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiologic consequences. However, the milder EFL1 variant was still solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligopyrimidine element–containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.",
author = "Sangmoon Lee and Shin, {Chang Hoon} and Jawon Lee and Jeong, {Seong Dong} and Hong, {Che Ry} and Kim, {Jun Dae} and Kim, {Ah Ra} and Boryeong Park and Son, {Soo Jin} and Oleksandr Kokhan and Taekyeong Yoo and Ko, {Jae Sung} and Sohn, {Young Bae} and Kim, {Ok Hwa} and Ko, {Jung Min} and Cho, {Tae Joon} and Wright, {Nathan T.} and Seong, {Je Kyung} and Jin, {Suk Won} and Kang, {Hyoung Jin} and Kim, {Hyeon Ho} and Murim Choi",
note = "Funding Information: This study was partly supported by grants 2014M3C9A2064686 and 2019R1A2C2010789 (M.C.) and 2017R1A2A2A05069691 (H.H.K.) from the National Research Foundation of Korea, and awards REU CHE-1062629 and RUI MCB-1607024 (N.T.W.) from the National Science Foundation. This research was partly supported by the Korea Mouse Phenotyping Project (2013M3A9D5072550) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. Funding Information: The authors thank the patients and families who participated in this study; Jung-Ah Kim and Hyoung-Jin Kim at Seoul National University Hospital and Cho-Rong Lee and Eunha Kim at Seoul National University for collecting and interpreting hematologic data and interpreting images; and the University of Utah Mutation Generation and Detection Core for development of the Efl1 knock-in mice. O.K. acknowledges the computing resources provided by Bebop, a high-performance computing cluster operated by the Laboratory Computing Resource Center at Argonne National Laboratory. This study was partly supported by grants 2014M3C9A2064686 and 2019R1A2C2010789 (M.C.) and 2017R1A2A2A05069691 (H.H.K.) from the National Research Foundation of Korea, and awards REU CHE-1062629 and RUI MCB-1607024 (N.T.W.) from the National Science Foundation. This research was partly supported by the Korea Mouse Phenotyping Project (2013M3A9D5072550) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",
year = "2021",
month = nov,
day = "25",
doi = "10.1182/blood.2021010913",
language = "English (US)",
volume = "138",
pages = "2117--2128",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "21",
}