Bibliographic Details
| Title: |
Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1 |
| Authors: |
Mao Lin, Zhenlei Liu, Gang Liu, Sen Zhao, Chao Li, Weisheng Chen, Zeynep Coban Akdemir, Jiachen Lin, Xiaofei Song, Shengru Wang, Qiming Xu, Yanxue Zhao, Lianlei Wang, Yuanqiang Zhang, Zihui Yan, Sen Liu, Jiaqi Liu, Yixin Chen, Yuzhi Zuo, Xu Yang, Tianshu Sun, Xin‐Zhuang Yang, Yuchen Niu, Xiaoxin Li, Wesley You, Bintao Qiu, Chen Ding, Pengfei Liu, Shuyang Zhang, Claudia M. B. Carvalho, Jennifer E. Posey, Guixing Qiu, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, James R. Lupski, Zhihong Wu, Jianguo Zhang, Nan Wu |
| Source: |
Molecular Genetics & Genomic Medicine, Vol 8, Iss 1, Pp n/a-n/a (2020) |
| Publisher Information: |
Wiley, 2020. |
| Publication Year: |
2020 |
| Collection: |
LCC:Genetics |
| Subject Terms: |
dominant‐negative mechanism, FBN1, Marfan syndrome, Marfanoid–progeroid–lipodystrophy syndrome, targeted next generation sequencing, Genetics, QH426-470 |
| More Details: |
Abstract Background The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid–progeroid–lipodystrophy syndrome (MPLS). Methods We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. Results We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense‐mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. Conclusion We provide direct evidence that a dominant‐negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2324-9269 |
| Relation: |
https://doaj.org/toc/2324-9269 |
| DOI: |
10.1002/mgg3.1023 |
| Access URL: |
https://doaj.org/article/5cbefdd21f0a45fc98c8888556471ceb |
| Accession Number: |
edsdoj.5cbefdd21f0a45fc98c8888556471ceb |
| Database: |
Directory of Open Access Journals |
