FBN1 – Progeroid and Marfanoid Aspect-Lipodystrophy Syndrome

Fibrillin-1 (FBN1) encodes a large extracellular matrix glycoprotein essential for microfibril assembly and elasticity. Heterozygous truncating or splice‐site variants in FBN1 have been identified in patients presenting with progeroid and marfanoid aspect–lipodystrophy syndrome (MPLS), a rare dominant fibrillinopathy characterized by tall stature, distinctive craniofacial features, and loss of subcutaneous fat. The emerging evidence supports a dominant-negative mechanism distinct from classical Marfan syndrome, emphasizing the need for targeted genetic testing in atypical fibrillinopathies.

Genetic studies have reported two unrelated, de novo FBN1 variants in MPLS: a splice-donor mutation c.8226+5G>A causing skipping of exon 65 and NMD escape (PMID:37845262), and a truncating alteration within the asprosin domain (c.6007G>A (p.Gly2003Arg)) in the first Chinese MPLS case (PMID:31774634). Both probands exhibited consistent features including tall stature, dolichocephaly, prominent forehead, narrow nasal ridge, high-arched palate, long fingers, and lipodystrophy. No familial segregation has been observed beyond the index cases.

The variant spectrum in MPLS currently comprises at least one canonical splice-site change (c.8226+5G>A) and one missense alteration (c.6007G>A (p.Gly2003Arg)). The c.8226+5G>A variant disrupts normal splicing of exon 65, while the c.6007G>A allele likely perturbs asprosin domain integrity. Both variants arose de novo and are absent from population databases, consistent with Mendelian dominant inheritance.

Functional assays demonstrate that c.8226+5G>A induces exon skipping, escapes nonsense-mediated decay, and results in a frameshifted transcript in patient mRNA (PMID:37845262). In vitro expression of MPLS truncating alleles shows impaired fibrillin aggregation and upregulation of SMAD2 phosphorylation compared with classical Marfan truncations, indicating aberrant TGF-β signalling and a dominant-negative effect (PMID:31774634).

Together, genetic and experimental data converge on a dominant-negative mechanism of pathogenicity for FBN1-related MPLS, distinct from haploinsufficiency or simple loss-of-function. The specific disruption of the asprosin domain and splice-altered transcripts underscore genotype-phenotype correlations within the fibrillin spectrum and guide molecular diagnosis and genetic counselling.

Key Take-home: Heterozygous splice and truncating FBN1 variants cause MPLS via dominant-negative effects confirmed by exon-skipping and cellular assays, enabling precise diagnosis, family planning, and potential TGF-β–targeted interventions.

References

• Human Genome Variation • 2023 • A case of Marfanoid-progeroid-lipodystrophy syndrome: experimental proof of skipping exons and escaping nonsense-mediated decay. PMID:37845262
• Molecular Genetics & Genomic Medicine • 2020 • Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1. PMID:31774634

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