This report describes Friedreich ataxia 1 (FRDA), which exhibits autosomal recessive inheritance. The human gene implicated in this disease is FXN, which encodes frataxin, a nuclear-encoded mitochondrial iron chaperone involved in iron-sulfur biogenesis and heme biosynthesis. The most common FRDA-related molecular abnormality is an expansion of a non-coding GAA triplet repeat in the first intron of the FXN gene. There is one high-scoring fly ortholog, fh for which an amorphic allele, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
UAS constructs of the wild-type human Hsap\FXN gene have been introduced into flies. Heterologous rescue (functional complementation) of Dmel\fh phenotypes has been demonstrated.
Animals homozygous for an amorphic allele of Dmel\fh die during late larval or pupal stages; somatic clones exhibit neuroanatomy and neurophysiology defects. A moderate loss of function, effect by RNAi, results in a shortened life span, reduced climbing abilities, and enhanced sensitivity to oxidative stress; loss of function targeted specifically to the developing heart results in cardiac defects. An expanded GAA triplet-repeat from the first intron of the human Hsap\FXN gene, with a GAA repeat length of about 200 units and obtained from the genomic DNA of a patient with FRDA, has been inserted into the intron of the Dmel\fh gene. These flies exhibit loss-of-function phenotypes. Genetic interactions of Dmel\fh have been described; see the fh gene report.
[updated Mar. 2021 by FlyBase; FBrf0222196]
[FRIEDREICH ATAXIA; FRDA](https://omim.org/entry/229300)
Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty. It is one of the most common forms of autosomal recessive ataxia, occurring in about 1 in 50,000 individuals. Other variable features include visual defects, scoliosis, pes cavus, and cardiomyopathy (review by Delatycki et al., 2000, pubmed:10633128). [From OMIM:229300, 2016.01.22]
Friedreich ataxia (FRDA1) is caused by mutation in FXN, the gene encoding frataxin. The most common molecular abnormality is a noncoding GAA trinucleotide repeat expansion in intron 1 of the FXN gene: normal individuals have 5 to 30 GAA repeat expansions, whereas affected individuals have from 70 to more than 1,000 GAA triplets (Al-Mahdawi et al., 2006, pubmed:16919418). 2% of cases of Friedreich ataxia are due to point mutations in the FXN gene (Delatycki et al., 1999, pubmed:10543403). [From OMIM:229300, 2016.01.22]
Frataxin is a nuclear-encoded mitochondrial iron chaperone involved in iron-sulfur biogenesis and heme biosynthesis. Some studies have also suggested that frataxin functions as an iron storage molecule, an antioxidant, and a tumor suppressor (summary by Schmucker et al., 2008,pubmed:18725397). [From OMIM:606829, 2016.01.22]
Ortholog of human FXN (1 Drosophila to 1 human).
Dmel\fh shares 42% identity and 57% similarity with human FXN.