Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.

TitleGenetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.
Publication TypeJournal Article
Year of Publication2020
AuthorsLin, M, Liu, Z, Liu, G, Zhao, S, Li, C, Chen, W, Akdemir, ZCoban, Lin, J, Song, X, Wang, S, Xu, Q, Zhao, Y, Wang, L, Zhang, Y, Yan, Z, Liu, S, Liu, J, Chen, Y, Zuo, Y, Yang, X, Sun, T, Yang, X-Z, Niu, Y, Li, X, You, W, Qiu, B, Ding, C, Liu, P, Zhang, S, Carvalho, CMB, Posey, JE, Qiu, G, Lupski, JR, Wu, Z, Zhang, J, Wu, N
Corporate AuthorsDeciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study
JournalMol Genet Genomic Med
Date Published2020 Jan
KeywordsAdolescent, Adult, Child, Female, Fibrillin-1, HEK293 Cells, Humans, Lipodystrophy, Marfan Syndrome, Mutation, Phenotype, Progeria, Protein Domains, Smad2 Protein

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.

Alternate JournalMol Genet Genomic Med
PubMed ID31774634
PubMed Central IDPMC6978264
Grant ListR01 NS058529 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States

Similar Publications