Friedreich Ataxia 1 (FXN)
| Dred_ID | RD00054 |
| OMIM ID | 229300 |
| Disease name | Friedreich Ataxia 1 |
| Alternative names | Friedreich Ataxia with Retained Reflexes Fdra Friedreich Spinocerebellar Ataxia Hereditary Spinal Sclerosis |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Eye diseases |
| Phenotype | NIH Rare Diseases: Friedreich ataxia is an inherited condition that affects the nervous system and causes movement problems. People with this condition develop impaired muscle coordination (ataxia) that worsens over time. Other features include the gradual loss of strength and sensation in the arms and legs, muscle stiffness (spasticity), and impaired speech. Many individuals have a form of heart disease called hypertrophic cardiomyopathy. Some develop diabetes, impaired vision, hearing loss, or an abnormal curvature of the spine (scoliosis). Most people with Friedreich ataxia begin to experience the signs and symptoms around puberty. This condition is caused by mutations in the FXN gene and is inherited in an autosomal recessive pattern.
OMIM: 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). Pandolfo (2008) provided an overview of Friedreich ataxia, including pathogenesis, mutation mechanisms, and genotype/phenotype correlation. (229300) |
| Miscellaneouse | OMIM: onset before adolescence most common inherited ataxia estimated carrier frequency 1/100 patients often nonambulatory by the mid-twenties major cause of death is heart failure average age at death is 37 years most common genetic abnormality is a (gaa)n trinucleotide repeat expansion in intron 1 of the fxn gene repeat expansions range from 70 to over 1,000 (normal 5 to 30 repeats) |
| Prevalence | 1-9/100000 (Europe),1-9/100000 (France),1-9/100000 (Italy),1-9/100000 (Spain),1-9/100000 (Finland),1-9/1000000 (Finland),1-9/1000000 (Portugal),1-9/100000 (United Kingdom),1-9/1000000 (Greece),1-9/100000 (Norway),1-9/100000 (Germany),1-9/1000000 (Sweden),1-9/1000000 (Czech Republic),1-9/100000 (Russian Federation) [source: MalaCards] |
| Inheritance | Autosomal recessive |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | FXN |
| Alias symbols | FA; X25; CyaY; FARR; FRDA |
| Gene name | frataxin |
| Gene map locus | 9q21.11; chr9:69,035,751-69,079,076(+) |
| Ensembl Gene ID | ENSG00000165060 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016] |
| Repeat unit | GAA |
| Normal repeat copies | 5-30 |
| Pathogenic repeat copies | ≥71 |
| Gene | FXN |
| Repeat location | intron |
| Chromosome locus | chr9:69037287-69037307 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | RNA |
| Possible toxicity | Al-Mahdawi et al. (2008) found decreased FXN expression in brain and heart tissue, at 23% and 65% of normal levels, respectively, in postmortem specimens from 2 FRDA patients compared to normal controls. Bisulfite sequence analysis showed consistent hypermethylation of CpG sites upstream of the GAA repeat region and hypomethylation of CpG sites downstream of the repeat region. The upstream GAA DNA methylation changes in both FRDA brain and heart were consistent with their proposed roles in inhibition of FXN transcription. The methylation profiles of Fxn transgenic mouse brain and heart tissues resembled the profiles of human tissue, with cerebellar tissues most affected in the brain. Chromatin immunoprecipitation analysis showed histone modifications in human FRDA brain tissue, with overall decreased histone H3K9 acetylation, particularly downstream of the GAA repeat, and increased H3K9 methylation. The findings suggested a major role for DNA methylation and histone changes in the inhibition of FXN transcription in tissues affected by the disorder, as well demonstrating the importance of epigenetic changes that affect heterochromatin structure. Al-Mahdawi et al. (2008) proposed that histone deacetylase (HDAC) inhibitors may be of therapeutic use by increasing acetylation of histones and thereby increasing FXN transcription in FRDA cells. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 24749505 |
| Authors | Evans-Galea MV, Pébay A, Dottori M, Corben LA, Ong SH, Lockhart PJ, Delatycki MB. |
| Title | Cell and Gene Therapy for Friedreich Ataxia: Progress to Date |
| Journal | Hum Gene Ther. |
| Year | 2014 |