1. Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome
- Author
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Jae Sung Ko, Seong Dong Jeong, Young Bae Sohn, Che Ry Hong, Taekyeong Yoo, Hyeon Ho Kim, Murim Choi, Tae Joon Cho, Nathan T. Wright, Soo Jin Son, Ah-Ra Kim, Boryeong Park, Suk-Won Jin, Ok Hwa Kim, Jun-Dae Kim, Hyoung Jin Kang, Sangmoon Lee, Jung Min Ko, Jawon Lee, Oleksandr Kokhan, Je Kyung Seong, and Chang Hoon Shin
- Subjects
Adult ,Male ,Models, Molecular ,Ribosomopathy ,Somatic cell ,Immunology ,Biology ,Biochemistry ,Ribosome assembly ,Chromosome 15 ,medicine ,Animals ,Humans ,Point Mutation ,Allele ,Child ,Allele frequency ,Alleles ,Ribonucleoprotein, U5 Small Nuclear ,Genetics ,Cell Biology ,Hematology ,SBDS ,Uniparental Disomy ,medicine.disease ,Peptide Elongation Factors ,Uniparental disomy ,Shwachman-Diamond Syndrome ,Mice, Inbred C57BL ,Child, Preschool ,Female - 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.
- Published
- 2021