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

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.

Premature aging disorders: A clinical and genetic compendium

“…218 Mental development is not affected in most cases. 225,226,228,229 The C-terminal propeptide of FBN1 encoded by these exons is also called asprosin, a hormone regulating energy metabolism. 230…”

“…A wide range of autosomal dominantly inherited connective tissue disorders such as Marfan syndrome (MIM #154700), familial ectopa lentis (MIM #129600), stiff skin syndrome (MIM #184900), Weill‐Marchesani syndrome (MIM #608328), geleophysic dysplasia (MIM #614185), and acromicric dysplasia (MIM #102370) result from mutations in the FBN1 gene. However, only heterozygous truncating mutations in the final exons 64 and 66 are known to cause marfanoid‐progeroid‐lipodystrophy syndrome 225,226,228,229 . The C‐terminal pro‐peptide of FBN1 encoded by these exons is also called asprosin, a hormone regulating energy metabolism 230 …”

“…The clinical phenotype of marfanoid-progeroid-lipodystrophy syndrome has been described in only a few patients worldwide. The typical triad is characterized by incomplete signs of Marfan syndrome, neonatal progeroid facial appearance and congenital generalized lipodystrophy, which in most cases does not involve the breast and the iliac region 225,226. Signs of Marfan syndrome mainly include lens dislocation, myopia, aortic root dilatation, mitral valve prolapse, dural ectasia, arachnodactyly, pectus excavatum, hyperextensible joints and scoliosis 227.…”

Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions

“…Asprosin, which is encoded by the FBN1 locus, has a role in the mediation of the lipodystrophy phenotype [ 48 ]. It is an orexigenic hormone induced by fasting and produced by WAT, and increases food consumption and body weight through Agouti-related protein neurons (AgRP), and accelerates the production of liver glucose, activating the G protein-cAMP-protein kinase A (PKA) pathway [ 16 , 17 ].…”

Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders

“…Many individuals affected with MFS have an asthenic body habitus. A subgroup of MFS patients classified as marfanoid progeroid lipodystrophy syndrome (MPLS) caused by mutations in the C-terminal domain of fibrillin-1 (Passarge et al 2016), exhibit a progeroid appearance and/or a lipodystrophic phenotype (Goldblatt et al 2011;Horn and Robinson 2011;Takenouchi et al 2013;Garg and Xing 2014;Jacquinet et al 2014;Lin et al 2019). Neonatal progeroid syndrome (NPS) can also be caused by C-terminal fibrillin-1 mutations and is characterized by lipodystrophy from birth and premature aging (O'Neill et al 2007;Romere et al 2016).…”