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

• Published in: Blood 2021-11, Vol.138 (21), p.2117-2128
• Main Authors: Lee, Sangmoon, Shin, Chang Hoon, Lee, Jawon, Jeong, Seong Dong, Hong, Che Ry, Kim, Jun-Dae, Kim, Ah-Ra, Park, Boryeong, Son, Soo Jin, Kokhan, Oleksandr, Yoo, Taekyeong, Ko, Jae Sung, Sohn, Young Bae, Kim, Ok-Hwa, Ko, Jung Min, Cho, Tae-Joon, Wright, Nathan T., Seong, Je Kyung, Jin, Suk-Won, Kang, Hyoung Jin, Kim, Hyeon Ho, Choi, Murim
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Animals; Child; Child, Preschool; Female; Humans; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Peptide Elongation Factors - genetics; Point Mutation; Ribonucleoprotein, U5 Small Nuclear - genetics; Shwachman-Diamond Syndrome - genetics; Uniparental Disomy - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021010913

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. •Somatic uniparental disomy in the bone marrow generated an EFL1 allele combination that confers selective advantages.•Nevertheless, the resulting homozygous EFL1 allele in the hematopoietic system is hypomorphic and still responsible for SDS features. [Display omitted]