ZFYVE27 – Hereditary Spastic Paraplegia

Evidence for the involvement of ZFYVE27 in hereditary spastic paraplegia (HSP) primarily derives from a German family study in which an autosomal dominant inheritance pattern was observed. A missense variant, c.572G>T (p.Gly191Val), was identified in affected individuals, with the mutation co‑segregating with the disease phenotype (PMID:16826525). Although the genetic evidence is limited to a single family, the observation of the variant in this context supports a potential role in disease causality. Additional large‑scale mutational analyses have surveyed multiple HSP genes, with ZFYVE27 being mentioned as a candidate albeit with a debated contribution (PMID:22554690).

Functional studies from the initial report provided further support by demonstrating that the mutant ZFYVE27 protein exhibits an aberrant intracellular localization and a markedly reduced ability to interact with spastin—a protein central to vesicular trafficking in neuronal cells (PMID:16826525). These in vitro findings, while promising, require further replication in independent cohorts to fully establish the pathogenic mechanism. Overall, the combined genetic and experimental evidence suggests a limited but noteworthy association between ZFYVE27 and autosomal dominant HSP, underscoring its potential utility in diagnostic evaluation and future therapeutic strategies.

References

• American journal of human genetics • 2006 • ZFYVE27 (SPG33), a novel spastin‑binding protein, is mutated in hereditary spastic paraplegia PMID:16826525
• Journal of the neurological sciences • 2012 • Hereditary spastic paraplegias with autosomal dominant, recessive, X‑linked, or maternal trait of inheritance PMID:22554690

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