Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome

Sangmoon Lee, Chang Hoon Shin, Jawon Lee, Seong Dong Jeong, Che Ry Hong, Jun Dae Kim, Ah Ra Kim, Boryeong Park, Soo Jin Son, Oleksandr Kokhan, Taekyeong Yoo, Jae Sung Ko, Young Bae Sohn, Ok Hwa Kim, Jung Min Ko, Tae Joon Cho, Nathan T. Wright, Je Kyung Seong, Suk Won Jin, Hyoung Jin KangHyeon Ho Kim, Murim Choi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2117-2128
Number of pages12
JournalBlood
Volume138
Issue number21
DOIs
StatePublished - Nov 25 2021

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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