title: The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.
abstract: Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C, and L182F, which occur in patients in association with GAA expansions. These cases, and a further five reported cases of point mutations causing FRDA, demonstrate that splicing, nonsense, or initiation codon mutations (which cause a complete absence of functional frataxin) are associated with a severe phenotype. Missense mutations, even in highly evolutionally conserved amino acids, may cause a mild or severe phenotype.
authors.affiliation: Murdoch Institute for Research into Birth Defects, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Forrest
authors.forename: M
authors.initials: M
authors.lastname: Knight
authors.forename: M B
authors.initials: MB
authors.lastname: Delatycki
authors.forename: D
authors.initials: D
authors.lastname: Paris
authors.forename: R
authors.initials: R
authors.lastname: Williamson
authors.forename: J
authors.initials: J
authors.lastname: King
authors.forename: L
authors.initials: L
authors.lastname: Yeung
authors.forename: N
authors.initials: N
authors.lastname: Nassif
authors.forename: G A
authors.initials: GA
authors.lastname: Nicholson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D004452:Echocardiography; D004562:Electrocardiography; D005091:Exons / Q000235:genetics; D005260:Female; D005621:Friedreich Ataxia / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation; D011237:Predictive Value of Tests; D017422:Sequence Analysis, DNA; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins