Frataxin Structure and Function

CASTRO IGNACIO; PIGNATARO FLORENCIA; SEWELL ELLIOTH; ESPECHE LUCIA; HERRERA GEORGINA; DAIN LILIANA; NADRA ALEJANDRO; SANTOS JAVIER

Macromolecular Protein Complexes II: Structure and Function, Subcellular Biochemistry 93, https://doi.org/10.1007/978-3-030-28151-9_13

J. R. Harris and J. Marles-Wright (eds.)

Año: 2019;

Friedreich?s Ataxia is a rare autosomal recessive genetic disease (ORPHA95),58 which is characterized by progressive degeneration and damage of the central and peripheral nervous systems. It has a prevalence of approximately 1:50,000, repre60 senting half of all the genetic ataxias and three-quarters of the inherited ataxias in individuals younger than 25 years of age (Pandolfo 2009). The first symptoms occur typically in 8?15-year-olds and some of the most common are ataxia of gait and limbs, absence of tendon reflexes, loss of position sense and dysarthria (alteration in the articulation of words). Remarkably, two-thirds of patients have hypertrophic cardiomyopathy at the time of diagnosis (Durr et al. 1996). The name of this ataxia comes from Dr. Nikolaus Friedreich (1825?1882) who described the disease in five articles published during the late 19th century (Koeppen 2013), presenting the clinical findings of patients with ?a severe hereditary disorder of the nervous system?. In these works, Dr. Friedreich identified the main features of the disease and highlighted that it is hereditary and that its onset usually occurs before puberty. It is worthy of mention that Dr. Friedreich described the existence of hypertrophic cardiomyopathy, which is now recognized as the main cause of deathin Friedreich?s ataxia.A hundred years later, in 1988, the genetic alteration responsible for this disease was localized in the long arm of chromosome 9 by Chamberlain and coworkers (Chamberlain et al. 1988, 1989); whereas in 1996, a gene termed X25, was identified in the critical region for the FRDA locus by Campuzano and coworkers (Campuzano et al. 1996). The X25 gene codes for a small protein of 210 amino acid residues that was named frataxin (FXN).In this seminal work, Campuzano and collaborators described the structure of theFXN gene and found that most patients with Friedreich?s Ataxia (98%) werehomozygous for a GAA trinucleotide expansion of 700?800 repeats in most of thecases, localized in the first intron of the gene (nowadays we also know that theexpansion ranges from 70 to more than 1000 GAA triplets in patients), while the85 first intron of the FXN gene in normal chromosomes contains up to 35 to 40 GAA triplets (Pandolfo 2006; Patel and Isaya 2001). Additionally, close to 2?5% of patients exhibit a compound genotype having an expansion in one allele and a point mutation in the other. The triplet expansion alters FXN gene transcription, decreasing its protein expression, which is essential for viability in mammals. Moreover, FXN has homologs in very distant organisms, like bacteria and yeast.Structural biology and biochemistry concerning this protein have advanced notably in several directions during the last two decades. In particular, during the last 10 years, there have been extremely interesting findings that have changed the paradigm regarding the function of FXN, placing FXN in a new macromolecular context.