FLNA – Frontometaphyseal Dysplasia

Filamin A (FLNA) is an X-linked actin-crosslinking protein whose gain-of-function mutations cause frontometaphyseal dysplasia (FMD), a sclerotic skeletal dysplasia characterized by hyperostosis of the skull, long bone modeling defects, and extraskeletal anomalies including cleft palate and joint contractures. FMD follows an X-linked dominant inheritance pattern with variable expressivity and reduced male viability.

Genetic analysis of 23 unrelated FMD probands, including 11 familial cases (total affected individuals 32), revealed FLNA mutations in 57% of patients, with missense substitutions clustering in the actin-binding domain and immunoglobulin-like repeats (n=13 distinct variants) ([PMID:16835913]). Segregation in 11 multiplex families demonstrated co-segregation of missense variants with disease in 9 additional affected relatives ([PMID:16835913]). Among reported alleles, c.733G>A (p.Glu245Lys) exemplifies a recurrent pathogenic change.

Variant spectrum comprises predominantly missense mutations (n=13) and in-frame deletions (e.g., c.4904_4912del (p.Arg1635_Val1637del)) affecting structural repeats, consistent with a gain-of-function effect. De novo occurrences are frequent in simplex cases, while familial instances exhibit skewed X-inactivation correlating with phenotypic severity.

Functional studies support a gain-of-function mechanism: the P2204L substitution in Ig20 destabilizes autoinhibition, leading to ligand-independent Ser-2152 phosphorylation and altered thermodynamic properties ([PMID:28348077]). Disease-associated FLNA mutations disrupt key protein‐protein interactions, including FLNA-PTPN12 binding and integrin β1-tail association, perturbing focal adhesion dynamics and small GTPase regulation ([PMID:26594644],[PMID:20332112]).

While FLNA mutations underlie most FMD cases, locus heterogeneity is evident: seven patients meeting FMD criteria lacked FLNA variants, implicating alternative genes in FMD-like phenotypes ([PMID:25899317]).

Collectively, FLNA gain-of-function variants demonstrate robust genetic and experimental evidence linking FLNA to frontometaphyseal dysplasia. Comprehensive FLNA sequencing is recommended for definitive molecular diagnosis of FMD.

Key take-home: FLNA pathogenic missense and in-frame deletion variants cause frontometaphyseal dysplasia via a gain-of-function mechanism, providing a clear target for genetic testing and counseling.

References

• American journal of medical genetics. Part A • 2006 • Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity. PMID:16835913
• The Journal of Biological Chemistry • 2017 • Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A. PMID:28348077
• Journal of cardiovascular development and disease • 2015 • MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions. PMID:26594644
• American journal of medical genetics. Part A • 2015 • Frontometaphyseal dysplasia and keloid formation without FLNA mutations. PMID:25899317

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