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 Publication2019
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
Paginatione1023
Date Published2019 Nov 27
ISSN2324-9269
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.

DOI10.1002/mgg3.1023
Alternate JournalMol Genet Genomic Med
PubMed ID31774634
Grant List7191007 / / Beijing Natural Science Foundation /
81972037 / / National Natural Science Foundation of China /
190038 / / the International Program Associate grant from RIKEN of Japan /
R35 NS105078 / NS / NINDS NIH HHS / United States
7184232 / / Beijing Natural Science Foundation /
NINDS R01 NS058529 / / the US National Institutes of Health, National Institute of Neurological Disorders and Stroke /
2016-I2M-2-006 / / CAMS Initiative for Innovative Medicine /
81972132 / / National Natural Science Foundation of China /
81772301 / / National Natural Science Foundation of China /
UM1 HG006542 / HG / NHGRI NIH HHS / United States
5184037 / / Beijing Natural Science Foundation /
K08 HG008986 / HG / NHGRI NIH HHS / United States
81902178 / / National Natural Science Foundation of China /
81822030 / / National Natural Science Foundation of China /
2016-I2M-3-003 / / CAMS Initiative for Innovative Medicine /
81672123 / / National Natural Science Foundation of China /
NHGRI K08 HG008986 / / the National Human Genome Research Institute /
2018RC31003 / / the Central Level Public Interest Program for Scientific Research Institute /
NHGRI/NHLBI UM1 HG006542 / / National Human Genome Research Institute/National Heart, Lung, and Blood Institute /
2016YFC0901501 / / the National Key Research and Development Program of China /
81930068 / / National Natural Science Foundation of China /
2017-I2M-2-001 / / CAMS Initiative for Innovative Medicine /
2018YFC0910506 / / the National Key Research and Development Program of China /
81772299 / / National Natural Science Foundation of China /
7172175 / / Beijing Natural Science Foundation /
81902271 / / National Natural Science Foundation of China /