#610244
Table of Contents
A number sign (#) is used with this entry because of evidence that spastic paraplegia-33 (SPG33) is caused by heterozygous mutation in the ZFYVE27 gene (610243) on chromosome 10q24. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Mannan et al. (2006) described a 5-generation German family with hereditary spastic paraplegia. Clinical features of affected members suggested that theirs was a pure form of SPG. 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 affected members of German family segregating spastic paraplegia, Mannan et al. (2006) identified a heterozygous 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 (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 SPG 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.
Mannan, A. U. Response to Martignoni et al. (Letter) Am. J. Hum. Genet. 83: 128-130, 2008.
Mannan, A. U., Krawen, P., Sauter, S. M., Boehm, J., Chronowska, A., Paulus, W., Neesen, J., Engel, W. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am. J. Hum. Genet. 79: 351-357, 2006. [PubMed: 16826525, images, related citations] [Full Text]
Martignoni, M., Riano, E., Rugarli, E. I. The role of ZFYVE27/protrudin in hereditary spastic paraplegia. (Letter) Am. J. Hum. Genet. 83: 127-128, 2008. [PubMed: 18606302, related citations] [Full Text]
DO: 0110784;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
10q24.2 | Spastic paraplegia 33, autosomal dominant | 610244 | Autosomal dominant | 3 | ZFYVE27 | 610243 |
A number sign (#) is used with this entry because of evidence that spastic paraplegia-33 (SPG33) is caused by heterozygous mutation in the ZFYVE27 gene (610243) on chromosome 10q24. One such family has been reported.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Mannan et al. (2006) described a 5-generation German family with hereditary spastic paraplegia. Clinical features of affected members suggested that theirs was a pure form of SPG. 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 affected members of German family segregating spastic paraplegia, Mannan et al. (2006) identified a heterozygous 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 (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 SPG 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.
Mannan, A. U. Response to Martignoni et al. (Letter) Am. J. Hum. Genet. 83: 128-130, 2008.
Mannan, A. U., Krawen, P., Sauter, S. M., Boehm, J., Chronowska, A., Paulus, W., Neesen, J., Engel, W. ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia. Am. J. Hum. Genet. 79: 351-357, 2006. [PubMed: 16826525] [Full Text: https://doi.org/10.1086/504927]
Martignoni, M., Riano, E., Rugarli, E. I. The role of ZFYVE27/protrudin in hereditary spastic paraplegia. (Letter) Am. J. Hum. Genet. 83: 127-128, 2008. [PubMed: 18606302] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.014]
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