Alternative titles; symbols
HGNC Approved Gene Symbol: ZFYVE26
SNOMEDCT: 764686003;
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38) : 14:67,728,892-67,816,590 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.1 | Spastic paraplegia 15, autosomal recessive | 270700 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1997) cloned ZFYVE26, which they designated KIAA0321. The deduced 1,542-amino acid protein shares weak homology with mouse Hgs (604375), a protein involved in cell signaling. RT-PCR detected ZFYVE26 expression in all tissues examined. Highest expression was in ovary, followed by placenta, lung, and kidney. In vitro-translated ZFYVE26 had an apparent molecular mass of more than 100 kD by SDS-PAGE.
Hanein et al. (2008) characterized full-length ZFYVE26. The 2,539-residue protein has a 9.7-kb mRNA transcript and is expressed in various human tissues, particularly adrenal gland, bone marrow, adult brain, fetal brain, lung, placenta, prostate, skeletal muscle, testis, thymus, and retina. In situ hybridization showed wider and stronger Zfyve26 expression in embryonic rat brain compared to adult rat brain, particularly in the spinal cord and cortical, cerebellar, thalamic, and hippocampal neuroepithelia. In COS-7 cells, ZFYVE26 colocalized partially with markers of endoplasmic reticulum and endosomes.
The ZFYVE26 gene contains 42 exons (Hanein et al., 2008).
By radiation hybrid analysis, Nagase et al. (1997) mapped the ZFYVE26 gene to chromosome 14.
The ZFYVE26 gene maps to chromosome 14q24.1 (Hanein et al., 2008).
By immunoprecipitation analysis of HeLa cells, Slabicki et al. (2010) showed that KIAA0415 (613653) exists in a core protein complex containing SPG11 (610844), SPG15 (ZFYVE26), C20ORF29 (AP5S1; 614824), and DKFZp761E198 (614367). Knockdown of KIAA0415, C20ORF29, or SPG15 in HeLa cells reduced homologous recombination in a test substrate, whereas knockdown of SPG11 or DKFZp761E198 had no effect. Knockdown of KIAA0415 also reduced homologous recombination in U2OS human osteosarcoma cells.
In affected individuals from 8 families with autosomal recessive spastic paraplegia-15 (SPG15; 270700), Hanein et al. (2008) identified 6 different homozygous mutations in the ZFYVE26 gene (see, e.g., 612012.0001-612012.0004). The families had previously been reported by Hughes et al. (2001), Elleuch et al. (2007), Casali et al. (2004), and Boukhris et al. (2008). All the mutations resulted in truncated proteins. The phenotype was somewhat variable, but generally characterized by lower limb spasticity, cognitive deterioration, axonal neuropathy, and white matter abnormalities.
Goizet et al. (2009) identified 12 different biallelic truncating mutations in the ZFYVE26 gene (see, e.g., 612012.0005-612012.0006) in affected members of 8 families with SPG15.
In affected members of 2 presumably unrelated families with spastic paraplegia (SPG15; 270700) from Ireland (Hughes et al., 2001) and Morocco (Elleuch et al., 2007), respectively, Hanein et al. (2008) identified a homozygous 4312C-T transition in exon 21 of the ZFYVE26 gene, resulting in an arg1438-to-ter (R1438X) substitution. Both families were consanguineous and not known to be related.
In affected members of a consanguineous Algerian family with spastic paraplegia (SPG15; 270700) previously reported by Elleuch et al. (2007), Hanein et al. (2008) identified a homozygous G-to-A transition (5485-1G-A) in intron 28 of the ZFYVE26 gene, resulting in a splice site mutation.
In affected members of a consanguineous Israeli Arab family with spastic paraplegia (SPG15; 270700) previously reported by Elleuch et al. (2007), Hanein et al. (2008) identified a homozygous 70-bp deletion (6702del) in exon 36 of the ZFYVE26 gene, resulting in a frameshift and premature termination.
In affected members of 2 consanguineous Tunisian families with spastic paraplegia (SPG15; 270700) reported by Boukhris et al. (2008), Hanein et al. (2008) identified a homozygous 1477C-T transition in exon 10 of the ZFYVE26 gene, resulting in a gln493-to-ter (Q493X) substitution. Haplotype analysis indicated a founder effect.
In affected members of a consanguineous Syrian family with spastic paraplegia (SPG15; 270700), Goizet et al. (2009) identified a homozygous 1-bp deletion (5036delT) in exon 26 of the ZFYVE26 gene, resulting in a frameshift and premature termination. The proband presented at age 4 years with mental retardation, and the disorder progressed to severe lower limb spasticity and dysarthria. Brain MRI showed thin corpus callosum and white matter hyperintensities.
In affected members of a consanguineous Turkish family with spastic paraplegia (SPG15; 270700), Goizet et al. (2009) identified a homozygous 5422C-T transition in exon 28 of the ZFYVE26 gene, resulting in a gln1808-to-ter (Q1808X) substitution. The proband presented at age 14 years with lower limb spasticity. Other features included mental retardation, nystagmus, and white matter hyperintensities on brain MRI.
Boukhris, A., Feki, I., Denis, E., Miladi, M. I., Brice, A., Mhiri, C., Stevanin, G. Spastic paraplegia 15: linkage and clinical description of three Tunisian families. Mov. Disord. 23: 429-433, 2008. [PubMed: 18098276] [Full Text: https://doi.org/10.1002/mds.21848]
Casali, C., Valente, E. M., Bertini, E., Montagna, G., Criscuolo, C., De Michele, G., Villanova, M., Damiano, M., Pierallini, A., Brancati, F., Scarano, V., Tessa, A., and 11 others. Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 62: 262-268, 2004. [PubMed: 14745065] [Full Text: https://doi.org/10.1212/wnl.62.2.262]
Elleuch, N., Bouslam, N., Hanein, S., Lossos, A., Hamri, A., Klebe, S., Meiner, V., Birouk, N., Lerer, I., Grid, D., Bacq, D., Tazir, M., Zelenika, D., Argov, Z., Durr, A., Yahyaoui, M., Benomar, A., Brice, A., Stevanin, G. Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families. Neurogenetics 8: 307-315, 2007. [PubMed: 17661097] [Full Text: https://doi.org/10.1007/s10048-007-0097-x]
Goizet, C., Boukhris, A., Maltete, D., Guyant-Marechal, L., Truchetto, J., Mundwiller, E., Hanein, S., Jonveaux, P., Roelens, F., Loureiro, J., Godet, E., Forlani, S., and 12 others. SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73: 1111-1119, 2009. [PubMed: 19805727] [Full Text: https://doi.org/10.1212/WNL.0b013e3181bacf59]
Hanein, S., Martin, E., Boukhris, A., Byrne, P., Goizet, C., Hamri, A., Benomar, A., Lossos, A., Denora, P., Fernandez, J., Elleuch, N., Forlani, S., Durr, A., Feki, I., Hutchinson, M., Santorelli, F. M., Mhiri, C., Brice, A., Stevanin, G. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am. J. Hum. Genet. 82: 992-1002, 2008. [PubMed: 18394578] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.004]
Hughes, C. A., Byrne, P. C., Webb, S., McMonagle, P., Patterson, V., Hutchinson, M., Parfrey, N. A. SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 56: 1230-1233, 2001. [PubMed: 11342696] [Full Text: https://doi.org/10.1212/wnl.56.9.1230]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Slabicki, M., Theis, M., Krastev, D. B., Samsonov, S., Mundwiller, E., Junqueira, M., Paszkowski-Rogacz, M., Teyra, J., Heninger, A.-K., Poser, I., Prieur, F., Truchetto, J., and 9 others. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 8: e1000408, 2010. Note: Electronic Article. [PubMed: 20613862] [Full Text: https://doi.org/10.1371/journal.pbio.1000408]