Ataxia with vitamin E deficiency is caused by mutations in the α-tocopherol transfer protein

Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS, INSERM, ULP), Illkirch, Strasbourg, France.
Nature Genetics (Impact Factor: 29.35). 03/1995; 9(2):141-5. DOI: 10.1038/ng0295-141
Source: PubMed

ABSTRACT Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurodegenerative disease which maps to chromosome 8q13. AVED patients have an impaired ability to incorporate alpha-tocopherol into lipoproteins secreted by the liver, a function putatively attributable to the alpha-tocopherol transfer protein (alpha-TTP). Here we report the identification of three frame-shift mutations in the alpha TTP gene. A 744delA mutation accounts for 68% of the mutant alleles in the 17 families analysed and appears to have spread in North Africa and Italy. This mutation correlates with a severe phenotype but alters only the C-terminal tenth of the protein. Two other mutations were found in single families. The finding of alpha TTP gene mutations in AVED patients substantiates the therapeutic role of vitamin E as a protective agent against neurological damage in this disease.

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    • "Founder mutations observed in Tunisia were also reported in populations from the Middle East such as the splice site mutation in the CA II gene responsible for carbonic anhydrase II deficiency in the Arabic peninsula [47] and the p.Q357R molecular defect in the UGT1A1 gene of the Crigler-Najjar type I syndrome in the Kuwaiti population [48]. In other cases, founder mutations are dispersed around the Mediterranean basin as illustrated by the c.744delA mutation in the TTPA gene of ataxia with isolated vitamin E deficiency [49] and the splice site defects in megaloblastic anemia 1 [50] and triple-A syndrome [51]. In other examples, the founder haplotypes are shared with populations from Europe and America, as for the Parkinson disease [52]. "
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    ABSTRACT: Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid and cost effective tool for molecular diagnosis. Indeed, our report should help designing appropriate measures for carrier screening, better evaluation of diseases burden and setting up of preventive measures at the regional level.
    Orphanet Journal of Rare Diseases 08/2012; 7(1):52. DOI:10.1186/1750-1172-7-52 · 3.36 Impact Factor
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    • "Another conserved residue in BCH domains is Lys271 (HsBNIP-2 BCH numbering), which corresponds to K239 in yeast Sec14p and R221 in αTTP. A missense mutation at K239 in Sec14p has been reported to abolish PtIns transfer activity [55], [63] and a R221 mutation in αTTP is associated with a hereditary disorder known as AVED (ataxia with vitamin E deficiency) [6], [54], [64]. Being a part of a ‘hinge unit’, K239 might also contribute to controlling the movements of the helical gate [55]. "
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    ABSTRACT: The CRAL_TRIO protein domain, which is unique to the Sec14 protein superfamily, binds to a diverse set of small lipophilic ligands. Similar domains are found in a range of different proteins including neurofibromatosis type-1, a Ras GTPase-activating Protein (RasGAP) and Rho guanine nucleotide exchange factors (RhoGEFs). Proteins containing this structural protein domain exhibit a low sequence similarity and ligand specificity while maintaining an overall characteristic three-dimensional structure. We have previously demonstrated that the BNIP-2 and Cdc42GAP Homology (BCH) protein domain, which shares a low sequence homology with the CRAL_TRIO domain, can serve as a regulatory scaffold that binds to Rho, RhoGEFs and RhoGAPs to control various cell signalling processes. In this work, we investigate 175 BCH domain-containing proteins from a wide range of different organisms. A phylogenetic analysis with ~100 CRAL_TRIO and similar domains from eight representative species indicates a clear distinction of BCH-containing proteins as a novel subclass within the CRAL_TRIO/Sec14 superfamily. BCH-containing proteins contain a hallmark sequence motif R(R/K)h(R/K)(R/K)NL(R/K)xhhhhHPs ('h' is large and hydrophobic residue and 's' is small and weekly polar residue) and can be further subdivided into three unique subtypes associated with BNIP-2-N, macro- and RhoGAP-type protein domains. A previously unknown group of genes encoding 'BCH-only' domains is also identified in plants and arthropod species. Based on an analysis of their gene-structure and their protein domain context we hypothesize that BCH domain-containing genes evolved through gene duplication, intron insertions and domain swapping events. Furthermore, we explore the point of divergence between BCH and CRAL-TRIO proteins in relation to their ability to bind small GTPases, GAPs and GEFs and lipid ligands. Our study suggests a need for a more extensive analysis of previously uncharacterized BCH, 'BCH-like' and CRAL_TRIO-containing proteins and their significance in regulating signaling events involving small GTPases.
    PLoS ONE 03/2012; 7(3):e33863. DOI:10.1371/journal.pone.0033863 · 3.23 Impact Factor
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    • "Tocopherols and tocotrienols (vitamin E) are among the most potent chain-breaking antioxidants known [1], and they play a central role for the functionality of a variety of cells and tissues, such as cerebellar, peripheral, and retinal neurons [2] [3]. Tocopherol is also the most effective natural antioxidant to protect cultivated neuronal cells from oxidative cell death [4] [5]. "
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    ABSTRACT: Tocopherol is believed to be the most potent naturally occurring chain-breaking antioxidant. Hence, its refined phenolic head group chromanol may represent an optimum evolutionary solution to the problem of free-radical chain reactions in the lipid bilayer. To test the universal validity of this assumption beyond phenolic head groups, we have synthesized aromatic amine analogues of vitamin E and trolox with otherwise closely matching physicochemical properties: NH-toc and NH-trox. We have found that NH-toc and NH-trox were significantly more potent free radical scavengers, lipid peroxidation inhibitors and cytoprotective agents than their phenolic templates, tocopherol and trolox. In a chemical sense, thus, the chromanol head group does not constitute a global optimum for the design of chain-breaking antioxidants.
    FEBS letters 01/2012; 586(6):711-6. DOI:10.1016/j.febslet.2012.01.022 · 3.17 Impact Factor
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