Electronic Resource
Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies
| العنوان: | Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies |
|---|---|
| المؤلفون: | Di Fede, E, Lettieri, A, Taci, E, Castiglioni, S, Rebellato, S, Parodi, C, Colombo, E, Grazioli, P, Natacci, F, Marchisio, P, Pezzani, L, Fazio, G, Milani, D, Massa, V, Gervasini, C, Di Fede E., Lettieri A., Taci E., Castiglioni S., Rebellato S., Parodi C., Colombo E. A., Grazioli P., Natacci F., Marchisio P., Pezzani L., Fazio G., Milani D., Massa V., Gervasini C. |
| بيانات النشر: | Springer country:DE 2024 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Histone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, 3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (HDAC4, HDAC6 and HDAC8) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a de novo frameshift variant in HDAC2 gene. We then investigated its molecular effects in lymphoblastoid cell lines (LCLs) derived from the patient compared to LCLs from healthy donors (HD). As the variant was predicted to be likely pathogenetic and to affect the sequence of nuclear localization signal, we performed immunocytochemistry and lysates fractionation, observing a nuclear mis-localization of HDAC2 compared to HD LCLs. In addition, HDAC2 total protein abundance resulted altered in patient, and we found that newly identified variant in HDAC2 affects also acetylation levels, with significant difference in acetylation pattern among patient #249, HD and RSTS cells and in expression of a known molecular target. Remarkably, RNA-seq performed on #249, HD and RSTS cells shows differentially expressed genes (DEGs) common to #249 and RSTS. Interestingly, our reported patient was clinically diagnosed with RSTS, a chromatinopathy which known causative genes encode for enzymes antagonizing HDACs. These results support the role of HDAC2 as causative gene for chromatinopathies, strengthening the genotype-phenotype correlations in this relevant group of disorders. |
| مصطلحات الفهرس: | HDAC2, chromatinopathies, variant, info:eu-repo/semantics/article |
| URL: | info:eu-repo/semantics/altIdentifier/pmid/38753158 info:eu-repo/semantics/altIdentifier/wos/WOS:001226727900001 volume:143 issue:6 firstpage:747 lastpage:759 numberofpages:13 journal:HUMAN GENETICS |
| الاتاحة: | Open access content. Open access content |
| ملاحظة: | STAMPA English |
| Other Numbers: | ITBAO oai:boa.unimib.it:10281/495900 10.1007/s00439-024-02675-0 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85193480415 1456740600 |
| المصدر المساهم: | BICOCCA OPEN ARCH From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1456740600 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |