PHACTR1 – West syndrome

The association between PHACTR1 and West syndrome has been evaluated as Strong based on ten unrelated probands with de novo heterozygous missense variants and concordant functional data. De novo occurrence in each case and consistent in vivo and in vitro functional assays provide compelling evidence for a causal role of PHACTR1 in infantile epileptic spasms syndrome (IESS).

Genetic evidence supports an autosomal dominant inheritance mode with de novo variants in all affected individuals. A total of 10 probands were reported: two in the original Brain study and eight in a recent cohort study of missense and one CNV ([PMID:30256902]; [PMID:38272663]). There is no evidence of familial segregation beyond de novo events (affected_relatives = 0).

Variant spectrum is dominated by missense changes clustering in the RPEL3 domain. Key recurrent examples include c.1499T>C (p.Leu500Pro) and c.1436A>T (p.Asn479Ile) affecting actin binding ([PMID:30256902]). Other pathogenic variants reported are c.1561C>T (p.Arg521Cys) and c.1553T>A (p.Ile518Asn) impairing PP1 or actin interactions. No loss-of-function or structural variants have been implicated in West syndrome to date.

Functional studies reveal a dominant negative mechanism. In the mouse cortex, Phactr1 knockdown causes migration defects during corticogenesis that are rescued by wild-type but not by mutant PHACTR1 alleles, and only the p.Arg521Cys mutant shows dominant negative effects on dendritic development ([PMID:30256902]). Electrophysiological recordings from Phactr1-deficient neurons demonstrate abnormal synaptic properties.

Structural and interaction analyses further corroborate pathogenesis: AlphaFold-Multimer modelling shows that missense variants disrupt overlapping G-actin and PPP1CA binding interfaces in RPEL3, consistent with impaired PP1 recruitment and actin regulation observed in patient-derived mutations ([PMID:38272663]).

In summary, multiple lines of genetic and experimental evidence converge to implicate heterozygous PHACTR1 missense mutations in the pathophysiology of West syndrome. The dominant negative effect on neuronal migration and synaptic function underpins a clear mechanism of disease.

Key take-home: De novo missense variants in PHACTR1 cause West syndrome via dominant negative disruption of PP1 and actin regulation, supporting genetic diagnosis and potential targeted therapeutic strategies.

References

• Brain • 2018 • De novo PHACTR1 mutations in West syndrome and their pathophysiological effects. PMID:30256902
• Journal of medical genetics • 2024 • Genotype and phenotype correlation of PHACTR1-related neurological disorders. PMID:38272663

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