FLNB – Larsen syndrome

Filamin B (FLNB) is an actin-crosslinking cytoskeletal protein whose heterozygous variants cause autosomal dominant Larsen syndrome. Characterized by large joint dislocations, craniofacial dysmorphism and variable carpal ossification, the association was first described in 2004 and has been replicated over 18 years of study.

Genetic evidence includes missense and small in-frame deletion variants in [FLNB] that are absent from controls. A series of 20 probands screened by sequencing revealed causative variants clustering in the actin-binding and repeat domains, including c.5071G>A (p.Gly1691Ser) (PMID:16801345). A separate cohort of 7 unrelated probands confirmed five novel missense changes and one in-frame deletion (PMID:27048506).

Segregation analysis across pedigrees demonstrates familial transmission of FLNB variants. In one family, p.Glu227Lys (c.679G>A) was identified in 3 of 4 affected members (PMID:30916490). In a three-generation kindred, an in-frame deletion c.5468_5470delAGG (p.Glu1823del) co-segregated with disease in all affected relatives (PMID:31836586).

Functional studies support a gain-of-function mechanism. Missense mutations in the actin-binding domain (e.g., W148R, M202V) enhance F-actin affinity in co-sedimentation assays (PMID:19505475). Mutations also induce cytoplasmic focal accumulations correlating with phenotype severity (PMID:22190451) and impair cell migration through aberrant F-actin clustering (PMID:26491051).

Together, genetic, segregation, and functional data provide definitive evidence that heterozygous FLNB variants cause Larsen syndrome via altered actin dynamics. The clustering of dominant missense and in-frame deletions in functional domains underscores a gain-of-function pathogenesis. No conflicting studies have been reported.

Key Take-home: FLNB variant testing is clinically useful for diagnosis and genetic counseling in patients with Larsen syndrome presenting with joint dislocations and craniofacial features.

References

• Journal of medical genetics | 2007 | A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. PMID:16801345
• BMC medical genetics | 2016 | Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients. PMID:27048506
• Molecular genetics & genomic medicine | 2019 | A case study of atypical Larsen syndrome with absent hallmark joint dislocations. PMID:30916490
• Cold Spring Harbor molecular case studies | 2019 | Novel in-frame FLNB deletion causes Larsen syndrome in a three-generation pedigree. PMID:31836586
• Journal of molecular biology | 2009 | Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains. PMID:19505475
• Human mutation | 2012 | Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity. PMID:22190451
• American journal of physiology. Cell physiology | 2016 | F-actin clustering and cell dysmotility induced by the pathological W148R missense mutation of filamin B at the actin-binding domain. PMID:26491051

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