Dataset Information

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

ABSTRACT: Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (P = .034) driven by an increased incidence of nonrelapse mortality (NRM; P = .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERT rare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

SUBMITTER: Reilly CR

PROVIDER: S-EPMC8432045 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Reilly Christopher R CR Myllymäki Mikko M Redd Robert R Padmanaban Shilpa S Karunakaran Druha D Tesmer Valerie V Tsai Frederick D FD Gibson Christopher J CJ Rana Huma Q HQ Zhong Liang L Saber Wael W Spellman Stephen R SR Hu Zhen-Huan ZH Orr Esther H EH Chen Maxine M MM De Vivo Immaculata I DeAngelo Daniel J DJ Cutler Corey C Antin Joseph H JH Neuberg Donna D Garber Judy E JE Nandakumar Jayakrishnan J Agarwal Suneet S Lindsley R Coleman RC

Blood 20210901 10

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients ...[more]

PMID: 34019641

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Project description:ObjectiveN-methyl-D-aspartate receptors are glutamate-gated ion channels that play a crucial role in brain function. Numerous inherited or de novo variants in the GRIN2A gene, encoding the GluN2A subunit of the receptor, have been identified in patients with epilepsy. In addition, it is worth noting that GRIN2A variants exhibit a strong correlation with epilepsy-aphasia syndromes, a group of age-dependent epileptic, cognitive, and language disorders with a characteristic electroencephalographic pattern.MethodsWhole exome sequencing was conducted in enrolled patients with epilepsy-aphasia syndromes, and GRIN2A variants were screened. The conservation of substituted residues, conformational changes of mutant subunits, and in silico predictions of pathogenicity were thoroughly assessed in our study. Functional alterations of the variants were examined using whole-cell voltage-clamp current recordings while the relative surface expression levels of subunit proteins were assessed via immunofluorescence assays. A summary of previously published GRIN2A missense variants was conducted to investigate the genotypic-phenotypic-functional correlations.ResultsTwo missense GRIN2A variants (c. 2482A >G/p. M828V, c. 2627 T >C/p. I876T) were identified, which are located in the transmembrane helix M4 and C-terminus domain of the GluN2A subunit, respectively. Both variants exhibited reduced current density of NMDARs and surface/total expression levels of GluN2A subunits, while M828V showed a decreased extent of desensitization as well. A further summary of the previously reported GRIN2A variants demonstrated that more variable phenotypes were observed for variants situated in the C-terminus domain or those with loss-of-function effects.SignificanceOur study expands the phenotypic and functional range of GRIN2A-related disorders. In order to optimally establish the domain-function-phenotype correlations in GRIN2A variants, it is imperative to gather a more extensive set of clinical and functional data.Plain language summaryThis study has identified two genetic variants of the GRIN2A gene in patients with epilepsy-aphasia syndrome. We assess the variants' harmfulness through a variety of functional experiments, including evaluating the expression level of the mutated protein and the resulting changes in electrophysiological activities. Also, we reviewed previously published papers about GRIN2A variants in epilepsy to learn more about the correlations between their locations, functional changes, and clinical manifestations.

Dataset Information

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Publications

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Similar Datasets

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