Identification of a novel AluSx-mediated deletion of exon 3 in the SBDS gene in a patient with Shwachman–Diamond syndrome

Costa, Elı́sio; Duque, Frederico; Oliveira, Jorge; Garcia, Paula; Gonçalves, Isabel; Diogo, Luísa; Santos, Rosário

doi:10.1016/j.bcmd.2007.02.002

Cited by 15 publications

(7 citation statements)

References 26 publications

(51 reference statements)

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“…The other patient with a large deletion had a deletion of exon 3; deletions in this region have been previously reported. 45 , 46 Our findings suggest investigation for large structural variants in patients with a single known SBDS PV without a second pathogenic allele may be required in order to identify the genetic etiology of SDS.…”

Section: Discussion/conclusionmentioning

confidence: 91%

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

et al. 2022

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Background and Objectives Shwachman Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities. Methods We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute’s (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort. Results PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258+2T>C and c.183_184TA>CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies. Conclusions SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management.

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Section: Discussion/conclusionmentioning

confidence: 91%

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

et al. 2022

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“…EGFP-SBDS and EGFP-truncated SBDS proteins were detected at the expected size (Fig. 1b) [3,6,9,12,[17][18][19][20][21][22][23][24][25][26][27][28]. However, 85% of mutation sites were found in the same position, referred to as hot spots, both c.183TA[CT and c.258?2T[C. Several diseaserelated mutations (i.e., C31W, K33E, N34I, L71P), which were found in Domain I, did not rescue the cell growth in yeast [6].…”

Section: N-terminal Domain I Is Responsible For Nuclear Localizationmentioning

confidence: 99%

Mislocalization or low expression of mutated Shwachman–Bodian–Diamond syndrome protein

et al. 2011

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Shwachman-Diamond syndrome (SDS) is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. Mutations in the SBDS gene are identified in most patients with SDS. Recent studies have shown that SBDS is involved in ribosome biogenesis and is localized to the nucleolus. The significance of cellular localization in SBDS is unknown, particularly as SBDS does not exhibit canonical nuclear localization signals. In this study, we have constructed wild-type deletion mutants of the critical domains and disease-associated mutants of the SBDS gene. These constructs were expressed in HeLa cells to explore the subcellular distribution of normal and mutant proteins. Wild-type SBDS was detected in the nucleus. However, constructs lacking N-terminal Domain I and two disease-associated mutants (C31W and N34I) failed to localize SBDS to the nucleus. Moreover, the amount of mutated SBDS protein was decreased. When N-terminal Domain I was overexpressed in HeLa cells, the localization of endogenous SBDS protein was changed from nuclei to cytosolic fraction. These data indicate that the N-terminal Domain I is responsible for nuclear localization. Furthermore, low expression of SBDS, as exhibited in some of the disease-associated mutants, may be associated with the pathogenesis of SDS.

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“…Most patients harbour the biallelic pathogenic variants c.183_184TA > CT (K62X) and c.258 + 2T > C (C84fsX3), which result in truncated forms of the protein within its first domain [3]. Less common mutations have also been reported throughout the gene including nonsense mutations, missense mutations, small deletions, indel conversions and splice-site mutations [3,4,5,6,7]. The SBDS gene is located in chromosome 7q11, and encodes for a protein structurally organized into three highly conserved domains [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

Interaction of the GTPase Elongation Factor Like-1 with the Shwachman-Diamond Syndrome Protein and Its Missense Mutations

Gijsbers

Montagut

Méndez-Godoy

et al. 2018

IJMS

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The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in the genes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPase known as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-association factor eIF6 from the surface of the pre-60S ribosomal subunit to promote the formation of mature ribosomes. SBDS missense mutations can either destabilize the protein fold or affect surface epitopes. The molecular alterations resulting from the latter remain largely unknown, although some evidence suggest that binding to EFL1 may be affected. We further explored the effect of these SBDS mutations on the interaction with EFL1, and showed that all tested mutations disrupted the binding to EFL1. Binding was either severely weakened or almost abolished, depending on the assessed mutation. In higher eukaryotes, SBDS is essential for development, and lack of the protein results in early lethality. The existence of patients whose only source of SBDS consists of that with surface missense mutations highlights the importance of the interaction with EFL1 for their function. Additionally, we studied the interaction mechanism of the proteins in solution and demonstrated that binding consists of two independent and cooperative events, with domains 2–3 of SBDS directing the initial interaction with EFL1, followed by docking of domain 1. In solution, both proteins exhibited large flexibility and consisted of an ensemble of conformations, as demonstrated by Small Angle X-ray Scattering (SAXS) experiments.

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Identification of a novel AluSx-mediated deletion of exon 3 in the SBDS gene in a patient with Shwachman–Diamond syndrome

Cited by 15 publications

References 26 publications

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features

Mislocalization or low expression of mutated Shwachman–Bodian–Diamond syndrome protein

Interaction of the GTPase Elongation Factor Like-1 with the Shwachman-Diamond Syndrome Protein and Its Missense Mutations

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