Somatic uniparental disomy mitigates the most damaging <i>EFL1</i> allele combination in Shwachman-Diamond syndrome

Lee, Sang Moon; Shin, Chang Hoon; Lee, Jawon; Jeong, Seong Dong; Hong, Che Ry; Kim, Jun Dae; Kim, Ahra; Park, Boryeong; Son, Soo Jin; Kokhan, Oleksandr; Yoo, Tae Kyung; 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

doi:10.1182/blood.2021010913

Cited by 16 publications

(18 citation statements)

References 36 publications

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“…These alterations are associated with milder hematological phenotypes and a lower risk of developing MDS and AML ( Pressato et al, 2012 ; Valli et al, 2019 ; Valli et al, 2013 ), suggesting that hematological phenotypes are primarily caused by the continued presence of Tif6 on ribosomes, which blocks subunit joining. In addition, there is an SDS-like syndrome caused by mutations in EFL1 ( Stepensky et al, 2017 ; Tan et al, 2018 ; Lee et al, 2021 ; Tan et al, 2019 ), which may similarly prevent the timely release of eIF6 from the nascent ribosome.…”

Section: Ribosome Assembly At a Glancementioning

confidence: 99%

Quality control ensures fidelity in ribosome assembly and cellular health

Parker

Karbstein

2023

Journal of Cell Biology

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The coordinated integration of ribosomal RNA and protein into two functional ribosomal subunits is safeguarded by quality control checkpoints that ensure ribosomes are correctly assembled and functional before they engage in translation. Quality control is critical in maintaining the integrity of ribosomes and necessary to support healthy cell growth and prevent diseases associated with mistakes in ribosome assembly. Its importance is demonstrated by the finding that bypassing quality control leads to misassembled, malfunctioning ribosomes with altered translation fidelity, which change gene expression and disrupt protein homeostasis. In this review, we outline our understanding of quality control within ribosome synthesis and how failure to enforce quality control contributes to human disease. We first provide a definition of quality control to guide our investigation, briefly present the main assembly steps, and then examine stages of assembly that test ribosome function, establish a pass–fail system to evaluate these functions, and contribute to altered ribosome performance when bypassed, and are thus considered “quality control.”

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Section: Ribosome Assembly At a Glancementioning

confidence: 99%

Quality control ensures fidelity in ribosome assembly and cellular health

Parker

Karbstein

2023

Journal of Cell Biology

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“…Less common mutations have also been reported throughout the gene including nonsense mutations, missense mutations, small deletions, indel conversions and splice-site mutations [ 10 , 11 , 12 , 13 , 14 ]. The rest of the patients (less than 10%) present clinical indications of SDS without having any pathogenic variants in SBDS but in other genes coding the proteins DNAJC21 [ 15 , 16 ], SRP54 [ 17 ] and EFL1 [ 18 , 19 , 20 , 21 ]. Importantly, the observed SBDS mutations result in a protein function drop that is responsible, when the SBDS levels are below a certain threshold, for a phenotype corresponding to the clinical manifestation of SDS.…”

Section: Introductionmentioning

confidence: 99%

A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS

Spinetti

Delre

Siliqi

et al. 2022

IJMS

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The Shwachman–Diamond Syndrome (SDS) is an autosomal recessive disease whose majority of patients display mutations in a ribosome assembly protein named Shwachman–Bodian–Diamond Syndrome protein (SBDS). A specific therapy for treating this rare disease is missing, due to the lack of knowledge of the molecular mechanisms responsible for its pathogenesis. Starting from the observation that SBDS single-point mutations, localized in different domains of the proteins, are responsible for an SDS phenotype, we carried out the first comparative Molecular Dynamics simulations on three SBDS mutants, namely R19Q, R126T and I212T. The obtained 450-ns long trajectories were compared with those returned by both the open and closed forms of wild type SBDS and strongly indicated that two distinct conformations (open and closed) are both necessary for the proper SBDS function, in full agreement with recent experimental observations. Our study supports the hypothesis that the SBDS function is governed by an allosteric mechanism involving domains I and III and provides new insights into SDS pathogenesis, thus offering a possible starting point for a specific therapeutic option.

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“…The approach of whole-exome sequencing (WES) has disclosed genetic heterogeneity for SDS. Indeed, biallelic mutations in DNAJ homolog subfamily C member 21 (DNAJC21) (Tummala et al, 2016;Dhanraj et al, 2017), in GTPase Elongation Factor-like (EFL1) (Stepensky et al, 2017;Tan et al, 2018;Tan et al, 2019;Lee et al, 2021), or heterozygous mutations in the 54-kDa signal recognition particle (SRP54) (Carapito et al, 2017) have been reported in association with SDS or SDS-like phenotype in some patients.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

Taha

Foroni²,

Valli³

et al. 2022

Front. Genet.

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Background: Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive ribosomopathy mainly characterized by exocrine pancreatic insufficiency, skeletal alterations, neutropenia, and a relevant risk of hematological transformation. At least 90% of SDS patients have pathogenic variants in SBDS, the first gene associated with the disease with very low allelic heterogeneity; three variants, derived from events of genetic conversion between SBDS and its pseudogene, SBDSP1, provided the alleles observed in about 62% of SDS patients.Methods: We performed a reanalysis of the available WES files of a group of SDS patients with biallelic SBDS pathogenic variants, studying the results by next bioinformatic and protein structural analysis. Parallelly, careful clinical attention was given to the patient focused in this study.Results: We found and confirmed in one SDS patient a germline heterozygous missense variant (c.100T>C; p.Phe34Leu) in the EIF6 gene. This variant, inherited from his mother, has a very low frequency, and it is predicted as pathogenic, according to several in silico prediction tools. The protein structural analysis also envisages the variant could reduce the binding to the nascent 60S ribosomal.Conclusion: This study focused on the hypothesis that the EIF6 germline variant mimics the effect of somatic deletions of chromosome 20, always including the locus of this gene, and similarly may rescue the ribosomal stress and ribosomal dysfunction due to SBDS mutations. It is likely that this rescue may contribute to the stable and not severe hematological status of the proband, but a definite answer on the role of this EIF6 variant can be obtained only by adding a functional layer of evidence. In the future, these results are likely to be useful for selected cases in personalized medicine and therapy.

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

Cited by 16 publications

References 36 publications

Quality control ensures fidelity in ribosome assembly and cellular health

Quality control ensures fidelity in ribosome assembly and cellular health

A Comparative Molecular Dynamics Study of Selected Point Mutations in the Shwachman–Bodian–Diamond Syndrome Protein SBDS

Case Report: Heterozygous Germline Variant in EIF6 Additional to Biallelic SBDS Pathogenic Variants in a Patient With Ribosomopathy Shwachman–Diamond Syndrome

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