دورية أكاديمية
An FBN1 deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family.
| العنوان: | An FBN1 deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family. |
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| المؤلفون: | Guo DC; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Duan X; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Mimnagh K; Department of Internal Medicine, WVU School of Medicine-Charleston Division (Retired), Morgantown, West Virginia, USA., Cecchi AC; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Marin IC; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Yu Y; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Velasco WV; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Lee K; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Zhu X; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Murdock DR; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA., Leal SM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Wheeler MM; Genome Sciences, University of Washington, Seattle, Washington, USA., Smith J; Genome Sciences, University of Washington, Seattle, Washington, USA., Bamshad MJ; Genome Sciences, University of Washington, Seattle, Washington, USA., Milewicz DM; Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA. |
| المصدر: | Clinical genetics [Clin Genet] 2023 Jun; Vol. 103 (6), pp. 704-708. Date of Electronic Publication: 2023 Mar 07. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Copenhagen, Munksgaard. |
| مواضيع طبية MeSH: | Marfan Syndrome*/genetics , Aortic Diseases*, Humans ; Fibrillin-1/genetics ; Mutation ; Phenotype |
| مستخلص: | Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies. (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) |
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| معلومات مُعتمدة: | R01 HL109942 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: FBN1; Marfan syndrome; heritable thoracic aortic disease; pseudoexon |
| المشرفين على المادة: | 0 (Fibrillin-1) 0 (FBN1 protein, human) |
| تواريخ الأحداث: | Date Created: 20230302 Date Completed: 20230503 Latest Revision: 20240603 |
| رمز التحديث: | 20240603 |
| مُعرف محوري في PubMed: | PMC10159920 |
| DOI: | 10.1111/cge.14322 |
| PMID: | 36861389 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1399-0004 |
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| DOI: | 10.1111/cge.14322 |