Protrudin is a membrane protein that regulates polarized vesicular trafficking in neurons. The protrudin gene (ZFYVE27) is mutated in a subset of individuals with hereditary spastic paraplegia (HSP), and protrudin is therefore also referred to as spastic paraplegia 33 (=SPG33) (PMID:24668814). The mutated ZFYVE27 protein shows an aberrant intracellular pattern in its tubular structure. Its interaction with spastin is severely affected. It is postulated that this specific mutation in ZFYVE27 affects neuronal intracellular trafficking in the corticospinal tract, which is consistent with the pathology of HSP (PMID:16826525).
Mannan et al. (2006) described a 5-generation German family with hereditary spastic paraplegia (HSP). Clinical features of affected members suggested that theirs was a pure form of HSP. The index patient had had pes equinus for many years ... Mannan et al. (2006) described a 5-generation German family with hereditary spastic paraplegia (HSP). Clinical features of affected members suggested that theirs was a pure form of HSP. The index patient had had pes equinus for many years when she noticed a gait disorder at age 50 years. She then manifested hyperreflexia and spasticity of the lower limbs, a positive Babinski sign, and ankle clonus. Sensitivity was normal. She later required a wheelchair and ultimately became bedridden. Her daughter and son also had pes equinus, spasticity of the legs, and gait disorder. Cognitive deficits or additional neurologic symptoms were not present.
In the German family with HSP described by them, Mannan et al. (2006) found a missense mutation in the ZFYVE27 gene (G191V; 610243.0001). The ZFYVE27 gene encodes a FYVE-finger domain protein that interacts with spastin (604277), the protein ... In the German family with HSP described by them, Mannan et al. (2006) found a missense mutation in the ZFYVE27 gene (G191V; 610243.0001). The ZFYVE27 gene encodes a FYVE-finger domain protein that interacts with spastin (604277), the protein mutant in spastic paraplegia-4 (182601). An in vivo immunoprecipitation assay showed that interaction of the mutant ZFYVE27 protein with spastin was severely impaired. Two spastic paraplegia loci map in the vicinity of the ZFYVE27 gene on 10q24.2: SPG9 (601162) on 10q23.3-q24.2, and SPG27 (609041) within 10q22.1-q24.1. Mannan et al. (2006) excluded the ZFYVE27 gene from both of these loci. Thus, the subtype of spastic paraplegia caused by mutation in the ZFYVE27 gene was designated SPG33. Martignoni et al. (2008) commented that they found no difference in the ability of wildtype or G191V mutant protrudin to extend neurites in cellular functional expression studies. The G191V-mutant protein was also found to interact with Rab11-GDP (605570) and spastin (604277), indicating that the mutation did not lead to loss of function. They stated that G191V (dbSNP rs35077384) had been identified as a SNP in several populations, with an allele frequency ranging from 0.008 to 0.067, thus casting doubt on its pathogenicity. Martignoni et al. (2008) proposed that SPG33 be removed from the list of HSP genes. Mannan (2008) replied that their study showed a decreased interaction between G191V-mutant protrudin and spastin and explained that discrepancies could be due to the different assays used or the variable effect of G191V-mutant protrudin in different ethnic populations.