FLNB – Atelosteogenesis type III

Atelosteogenesis type III is a rare autosomal dominant skeletal dysplasia characterized by absent or hypoplastic long bones, vertebrae, and ribs, with joint dislocations and disharmonious skeletal maturation. Heterozygous missense variants in the gene encoding filamin B FLNB disrupt cytoskeletal scaffolding, causing perinatal lethality in severe cases and surviving forms in AOIII (PMID:27258362).

Genetic evidence for the association includes 15 unrelated probands harboring 14 novel missense variants clustering in the CH2 actin-binding domain and repeat 6 regions of filamin B, consistent with autosomal dominant inheritance (PMID:16752402). No additional affected relatives were reported, suggesting de novo occurrences in most cases.

The variant spectrum in AOIII is dominated by missense alleles, including c.4805C>G (p.Ser1602Cys) affecting the C-terminal repeat region. These substitutions localize to two mutational hotspots in exons 2–3 and 28–29, indicating critical domains for normal skeletogenesis.

Functional studies demonstrate a gain-of-function mechanism: X-ray crystallography and co-sedimentation assays of the ABD mutants W148R and M202V reveal preserved domain architecture yet a 3–13-fold increase in F-actin binding affinity, supporting enhanced cytoskeletal crosslinking (PMID:19505475).

Cellular analyses of FLNB mutants show actin-filamin focal aggregates and impaired cytoskeletal dynamics in vitro, correlating with the severity of AOIII phenotypes and confirming pathogenic clustering in the ABD and hinge regions (PMID:22190451).

Together, robust case-level data and concordant experimental evidence support a strong gene–disease association between FLNB and Atelosteogenesis type III. This underpins molecular diagnosis and genetic counselling in affected families.

References

• Journal of pediatric orthopedics. Part B • 2017 • Atelosteogenesis type III: orthopedic management. PMID:27258362
• Human Mutation • 2006 • Mutations in two regions of FLNB result in atelosteogenesis I and III. PMID:16752402
• 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 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

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