%0 Journal Article
%T Friedreich's Ataxia, Frataxin, PIP5K1B: Echo of a Distant Fracas
%A Aur¨¦lien Bayot
%A Pierre Rustin
%J Oxidative Medicine and Cellular Longevity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/725635
%X ¡°Frataxin fracas¡± were the words used when referring to the frataxin-encoding gene (FXN) burst in as a motive to disqualify an alternative candidate gene, PIP5K1B, as an actor in Friedreich's ataxia (FRDA) (Campuzano et al., 1996; Cossee et al., 1997; Carvajal et al., 1996). The instrumental role in the disease of large triplet expansions in the first intron of FXN has been thereafter fully confirmed, and this no longer suffers any dispute (Koeppen, 2011). On the other hand, a recent study suggests that the consequences of these large expansions in FXN are wider than previously thought and that the expression of surrounding genes, including PIP5K1B, could be concurrently modulated by these large expansions (Bayot et al., 2013). This recent observation raises a number of important and yet unanswered questions for scientists and clinicians working on FRDA; these questions are the substratum of this paper. 1. Friedreich¡¯s Ataxia With an estimated prevalence of 1£¿:£¿50,000 and a carrier frequency of about 1£¿:£¿60 to 1£¿:£¿90, Friedreich¡¯s ataxia (FRDA) is the most commonly inherited ataxia in the Caucasian population [1, 2]. It is a multisystemic, degenerative disease typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, loss of position and vibration sense, and speech and listening difficulties [3]. A majority of the affected individuals have hypertrophic cardiomyopathy. Glucose intolerance and diabetes mellitus are observed in a subset (about 30%) of cases. The onset of symptoms is usually between 10 and 15 years of age, but either much earlier or later onset has been infrequently observed. Initial symptoms can be purely neurological, but occasionally, cardiomyopathy can be the presenting symptom. Altogether, atypical presentations represent as much as 25% of the cases [4]. 2. The Molecular Mechanism In more than 98% of the cases, the disease originates from large homozygous GAA repeat expansions (66 to 1700 repeats; normal: 5 to 33, with 85% less than 12) in the first intron of FXN encoding a mitochondrial matrix targeted protein, frataxin. In between uninterrupted expansions, 34 to 66 represent premutation, or borderline alleles, at risk for intergenerational expansion. The few residual cases represent compound heterozygous for an expanded allele and a point mutation, most frequently a null mutation [5]. 3. Frataxin Depletion: Iron-Sulfur Cluster Deficiency Simultaneously to the discovery of the molecular basis of FRDA by the European consortium combining the teams
%U http://www.hindawi.com/journals/omcl/2013/725635/