Friedreich‐like ataxia with retinitis pigmentosa caused by the His¹⁰¹Gln mutation of the α‐Tocopherol transfer protein gene

Abstract

The alpha-tocopherol transfer protein (alpha-TTP) is a cytosolic liver protein that is presumed to function in the intracellular transport of alpha-tocopherol, the most biologically active form of vitamin E. We studied 4 unrelated patients with autosomal recessive Friedreich-like ataxia who had isolated vitamin E deficiency. A point mutation was identified in all of them at position 101 of the gene for alpha-TTP, where histidine (CAT) was replaced with glutamine (CAG). Three of the 4 patients developed retinitis pigmentosa subsequent to the onset of ataxia. Neurological symptoms included ataxia, dysarthria, hyporeflexia, and decreased proprioceptive and vibratory sensations. Electrophysiological and pathological examinations showed that the cardinal sites affected were the central axons of dorsal root ganglion cells and the retina, with minor involvement of the peripheral sensory nerve, optic nerve, and pyramidal tract. The vitamin E tolerance test performed showed that the absorption of vitamin E was normal but that its decrease from the serum was accelerated. Oral administration of vitamin E appeared to halt the progression of visual and neurological symptoms. We propose a new treatable syndrome of Friedreich-like ataxia and retinitis pigmentosa caused by a defect in the alpha-TTP gene.

Complexity of vitamin E metabolism

“…As α-TTP is also abundantly expressed in the placenta, the importance of α-TOH in preventing fetus resorption is evident [98] . Furthermore, α-TTP is also expressed in several other tissues [76] , such as rat brain, spleen, lung and kidney [99] , the pregnant mouse uterus [100] , retina [101] and central nervous system [21] , suggesting an ubiquitous role for α-TTP in intra-organ trafficking [102] . Hosomi et al [103] estimated the relative affinities of α-TTP to the different vitamin E forms and stereoisomers starting from RRR-α-TOH set to 100%: β-TOH (38%), α-T3 (12%), SRR-α-TOH (11%), γ-TOH and trolox (9%) followed by δ-TOH, α-TOH acetate and α-TOH quinone with 2%.…”

Crystal structure of human α-tocopherol transfer protein bound to its ligand: Implications for ataxia with vitamin E deficiency

“…Several mutations in the gene encoding ATTP, which result in a late-onset spinocerebellar ataxia, have been described (6,7,(26)(27)(28)(29)(30)(31). As the phenotype is recessive, the simplest explanation is that the disease results in a loss of function of ATTP.…”

“…The importance of ATTP in ␣-T homeostasis became apparent when mutations in ATTP were found to cause ataxia with vitamin E deficiency (AVED), an autosomal recessive disease in which degeneration of neurons results in a progressive spinocerebellar ataxia (6). Mutations in ATTP were also found to cause retinitis pigmentosa (7). ATTP is a cytosolic protein expressed mainly in the liver (8), and heterologous expression of ATTP in cell culture confers the ability to secrete ␣-T through a secretory pathway that is brefeldin A insensitive (9).…”

Mechanisms of Ligand Transfer by the Hepatic Tocopherol Transfer Protein

“…Multiple mutations in the ttpA gene were identified in AVED patients, which are thought to impair the cellular activities of the protein. Substitution mutations such as R59W, E141K, and R221W cause an early onset, severe form of the AVED syndrome, whereas the H101Q, A120T, and R192H substitutions are associated with a later onset, milder form of the disorder (13)(14)(15)(16)(17)(18)(19). Because these mutations have different effects on the protein intermembrane transfer and secretion activities (20,21), they represent useful tools with which to study the molecular mechanisms underlying ␣TTP function.…”