Alternative titles; symbols
HGNC Approved Gene Symbol: TTPA
Cytogenetic location: 8q12.3 Genomic coordinates (GRCh38): 8:63,058,409-63,086,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q12.3 | Ataxia with isolated vitamin E deficiency | 277460 | Autosomal recessive | 3 |
Using rat alpha-Ttp to screen a liver cDNA library, followed by PCR, Arita et al. (1995) cloned full-length human alpha-TTP. The deduced 278-amino acid protein has a calculated molecular mass of 31.7 kD and shares 94% identity with rat alpha-Ttp. Northern blot analysis of several human tissues detected a 4.5-kb alpha-TTP transcript in liver only.
Arita et al. (1995) found that recombinant human alpha-TTP transferred alpha-tocopherol from liposomes to the heavy membrane fraction.
Kono et al. (2013) found that wildtype TTPA bound phosphatidylinositol phosphates (PIPs), whereas the arginine mutants that cause ataxia with vitamin E deficiency in humans did not. In addition, PIPs in the target membrane promoted the intermembrane transfer of alpha-tocopherol by TTPA.
Crystal Structure
Kono et al. (2013) determined the crystal structure of the TTPA-PIP complex, which revealed that disease-related arginine residues interacted with the phosphate groups of the PIPs and that the PIPs' binding caused the lid of the alpha-tocopherol-binding pocket to open. Kono et al. (2013) concluded that PIPs have a role in promoting the release of a ligand from a lipid transfer protein.
By Southern blot hybridization of human/hamster somatic cell hybrid lines and fluorescence in situ hybridization, Arita et al. (1995) identified a single TTP1 gene in the chromosome 8q13.1-q13.3 region.
The role of TTP1 in vitamin E homeostasis, coupled with the mapping of ataxia with isolated vitamin E deficiency (AVED; 277460) also to 8q, prompted Ouahchi et al. (1995) to investigate a possible role of the TTP1 gene in that disorder. A mutation search of the TTP1 gene was made in 17 unrelated AVED families. In 15 families, the patients were homozygous for the linked haplotype, in agreement with known consanguinity in 12 cases and suggesting ancient consanguinity in the 3 remaining ones. In 68% of the mutant alleles in the 17 families analyzed, deletion of a single A at position 744 was found to have resulted in the replacement of the last 30 amino acids of the protein product by an aberrant 14 amino acid peptide. The mutation was referred to as Mediterranean because it appeared to have spread in North Africa and Italy. Two other independent frameshift mutations were found in patients of northern European ancestry.
Robinson et al. (1982) found in experiments in animals that diets deficient in vitamin E cause retinitis pigmentosa. For this reason, Yokota et al. (1996) studied the TTPA gene in 2 unrelated patients, a 60-year-old woman (patient 1) and a 47-year-old man (patient 2), who had autosomal recessive retinitis pigmentosa and low serum vitamin E concentrations. In both patients they found a his101-to-gln mutation (600415.0002). Initial visual symptoms were night blindness in patient 1, which began at the age of 43 years, and loss of peripheral vision in patient 2, which began at the age of 45 years. This patient also had mild ataxia, decreased vibration sense, and hyporeflexia. In each, ophthalmoscopy showed the typical changes for retinitis pigmentosa, Goldmann perimetry revealed a ring scotoma, and electroretinography showed no light-evoked electrical responses.
Cavalier et al. (1998) reported identification of 13 mutations in the TTPA gene in 27 families with AVED. Four mutations were found in 2 or more independent families: 744delA (600415.0001), which is the major mutation in North Africa, and 513insTT, 486delT, and arg134 to ter, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the TTPA gene revealed differences from Friedreich ataxia (229300): cardiomyopathy was found in 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represented the largest group of patients and mutations reported for this often misdiagnosed disease and pointed to the need for an early differential diagnosis from Friedreich ataxia in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.
Cellini et al. (2002) reported a patient with progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, as well as cerebellar atrophy and vitamin E deficiency. She had expanded CTA/CAG repeats suggestive of SCA8 (608768) and also had compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Supplementation with vitamin E did not improve symptoms. Cellini et al. (2002) suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit.
Although lipid peroxidation in the subendothelial space had been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remained uncertain. Terasawa et al. (2000) showed that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the alpha-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. Ttpa -/- mice present a useful genetic model of vitamin E deficiency.
Using differential analysis, Vasu et al. (2007) compared gene expression in heart tissue of Attp -/- mice with that of wildtype mice. Of the 65 genes affected by Attp deletion, a cluster of genes related to immune function were downregulated, whereas genes related to lipid metabolism and inflammatory response were upregulated. Classic antioxidant genes showed no significant change in expression in Attp -/- mice.
In 68% of the mutant alleles in 17 families with AVED (277460), Ouahchi et al. (1995) found a deletion of 1 bp (A) at position 744. The mutation, referred to as Mediterranean, appeared to have spread in North Africa and Italy.
Gotoda et al. (1995) found a missense mutation in the TTP1 gene in a 70-year-old man who had been well until the age of 52 years when he became aware of unsteadiness in the dark. At the age of 57, he began to have difficulty speaking. Thereafter ataxia and dysarthria progressed very slowly. At the age of 62 years, he was found to have extremely low serum vitamin E concentrations (Yokota et al., 1987); his parents and children, all of whom were neurologically normal, were found to have concentrations that were low or below normal. Improvement or stabilization of his neurologic dysfunction and symptoms occurred with administration of large doses of alpha-tocopherol acetate. The man came from a small, isolated island located 290 km from the mainland of Japan, where his family had lived for many generations. The proband was found to be homozygous for a T-to-G transversion at nucleotide 303 of the TTP1 cDNA, predicted to result in replacement of histidine (CAT) with glutamine (CAG) as residue 101. The his101-to-gln substitution could be detected by the fact that it disrupted a restriction site for NcoI. A mutant allele was not detected in 150 unrelated Japanese subjects living in Tokyo; however, of 801 island inhabitants, 21 were heterozygous for the his101-to-gln mutation. All 21 were asymptomatic and had normal physical examinations, and none was known to be related to the patient. On the average, heterozygotes had serum vitamin E concentrations 25% lower than those in normal subjects.
Yokota et al. (1996) demonstrated that retinitis pigmentosa is also a feature of this mutation.
Hentati et al. (1996) found a severely affected patient with ataxia and peripheral neuropathy (277460) who had deletion of nucleotide 485 in the TTPA gene. The deletion resulted in a frameshift and generation of a premature stop codon at residue 176.
Hentati et al. (1996) found a patient severely affected with ataxia and peripheral neuropathy (277460) who was homozygous for insertion of 2 thymine residues at nucleotide position 513 of their TTPA sequence, causing a frameshift and a premature stop codon.
Hentati et al. (1996) found a mildly affected patient with vitamin E deficiency (277460) who was a compound heterozygote for a 574G-A point mutation resulting in an arg192-to-his amino acid substitution, and the 513insTT TT mutation (600415.0004).
In 2 independent Canadian families with AVED (277460), Cavalier et al. (1998) found a truncating arg134-to-ter mutation in homozygous state in 1 patient with consanguineous parents and in compound heterozygous state with the 486delT mutation in the second nonconsanguineous family.
In a patient with ataxia and vitamin E deficiency (277460), Schuelke et al. (1999) identified a homozygous 552G-A mutation in the TTPA gene. Both parents were heterozygous for the mutation. The mutation did not cause an exchange of amino acids, but at the mRNA level, Schuelke et al. (1999) demonstrated that its position within a splice donor site led to abnormal splicing. Because liver tissue was not available for mRNA preparation, the authors amplified illegitimate transcripts from lymphoblastoid cells. In all mRNA transcripts, exon 3 was missing. In both parents, they detected both intact and truncated mRNA copies. The missplicing caused a shift in the reading frame with an aberrant amino acid sequence from codon 120 onward to a premature stop at codon 134. The truncated protein completely lacked the domains encoded by exons 3 to 5.
Arita, M., Sato, Y., Miyata, A., Tanabe, T., Takahashi, E., Kayden, H. J., Arai, H., Inoue, K. Human alpha-tocopherol transfer protein: cDNA cloning, expression and chromosomal localization. Biochem. J. 306: 437-443, 1995. [PubMed: 7887897] [Full Text: https://doi.org/10.1042/bj3060437]
Cavalier, L., Ouahchi, K., Kayden, H. J., Di Donato, S., Reutenauer, L., Mandel, J.-L., Koenig, M. Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am. J. Hum. Genet. 62: 301-310, 1998. [PubMed: 9463307] [Full Text: https://doi.org/10.1086/301699]
Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S. A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia. Arch. Neurol. 59: 1952-1953, 2002. [PubMed: 12470185] [Full Text: https://doi.org/10.1001/archneur.59.12.1952]
Gotoda, T., Arita, M., Arai, H., Inoue, K., Yokota, T., Fukuo, Y., Yazaki, Y., Yamada, N. Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the alpha-tocopherol-transfer protein. New Eng. J. Med. 333: 1313-1318, 1995. [PubMed: 7566022] [Full Text: https://doi.org/10.1056/NEJM199511163332003]
Hentati, A., Deng, H.-X., Hung, W.-Y., Nayer, M., Ahmed, M. S., He, X., Tim, R., Stumpf, D. A., Siddique, T. Human alpha-tocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann. Neurol. 39: 295-300, 1996. [PubMed: 8602747] [Full Text: https://doi.org/10.1002/ana.410390305]
Kono, N., Ohto, U., Hiramatsu, T., Urabe, M., Uchida, Y., Satow, Y., Arai, H. Impaired alpha-TTP-PIPs interaction underlies familial vitamin E deficiency. Science 340: 1106-1110, 2013. [PubMed: 23599266] [Full Text: https://doi.org/10.1126/science.1233508]
Ouahchi, K., Arita, M., Kayden, H., Hentati, F., Ben Hamida, M., Sokol, R., Arai, H., Inoue, K., Mandel, J.-L., Koenig, M. Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nature Genet. 9: 141-145, 1995. [PubMed: 7719340] [Full Text: https://doi.org/10.1038/ng0295-141]
Robinson, W. G., Kuwabara, T., Bieri, J. G. The role of vitamin E and unsaturated fatty acids in the visual process. Retina 2: 263-281, 1982. [PubMed: 6101134]
Schuelke, M., Mayatepek, E., Inter, M., Becker, M., Pfeiffer, E., Speer, A., Hubner, C., Finckh, B. Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency. J. Pediat. 134: 240-244, 1999. [PubMed: 9931538] [Full Text: https://doi.org/10.1016/s0022-3476(99)70424-5]
Terasawa, Y., Ladha, Z., Leonard, S. W., Morrow, J. D., Newland, D., Sanan, D., Packer, L., Traber, M. G., Farese, R. V., Jr. Increased atherosclerosis in hyperlipidemic mice deficient in alpha-tocopherol transfer protein and vitamin E. Proc. Nat. Acad. Sci. 97: 13830-13834, 2000. [PubMed: 11095717] [Full Text: https://doi.org/10.1073/pnas.240462697]
Vasu, V. T., Hobson, B., Gohil, K., Cross, C. E. Genome-wide screening of alpha-tocopherol sensitive genes in heart tissue from alpha-tocopherol transfer protein null mice (ATTP-/-). FEBS Lett. 581: 1572-1578, 2007. [PubMed: 17382327] [Full Text: https://doi.org/10.1016/j.febslet.2007.03.017]
Yokota, T., Shiojiri, T., Gotoda, T., Arai, H. Retinitis pigmentosa and ataxia caused by a mutation in the gene for the alpha-tocopherol-transfer protein. (Letter) New Eng. J. Med. 335: 1770-1771, 1996. [PubMed: 8965888] [Full Text: https://doi.org/10.1056/NEJM199612053352315]
Yokota, T., Wada, Y., Furukawa, T., Tsukagoshi, H., Uchihara, T., Watabiki, S. Adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency. Ann. Neurol. 22: 84-87, 1987. [PubMed: 3477125] [Full Text: https://doi.org/10.1002/ana.410220119]