Decoding disease diversity: the impact of missense mutations on FLVCR1 isoforms and their interaction networks.

Mutations in the FLVCR1 gene underlie a remarkably wide range of rare human diseases: from retinitis pigmentosa, which causes progressive vision loss, to posterior column ataxia of the spinal cord, which impairs balance, and even mixed forms combining both conditions. Other manifestations include hereditary sensory and autonomic neuropathy, which damages the nerves and involuntary functions; Diamond–Blackfan–like syndromes, characterised by severe anemia and skeletal malformations; and congenital hydrocephalus, an excessive accumulation of fluid in the brain. Although some symptoms overlap, we still lack a unifying model that explains their common underlying mechanism. FLVCR1 encodes two versions of the same protein: FLVCR1a, which is localised at the cell membrane, and FLVCR1b, which resides in the mitochondria, the cell’s “power plants.” The current debate about which molecules FLVCR1a actually transports, together with our limited understanding of FLVCR1b’s role, have so far hindered clear insight into how specific mutations produce such different clinical scenario and have slowed the development of targeted therapies. Our project aims to fill these gaps by conducting detailed molecular studies of both isoforms and investigating the functional impact of each genetic variant. In doing so, we will unravel why similar mutations lead to distinct diseases and lay the foundation for personalised treatments to correct the altered cellular function.