Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia

• DOI: 10.1002/ana.24595
• Publication Date: 2015-12-24T17:35:58Z
• Authors: Charles A. Galea; Aamira Huq; Paul J. Lockhart; Geneieve Tai; Louise A. Corben; Eppie M. Yiu; Lyle C. Gurrin; David R. Lynch; Sarah Gelbard; Alexandra Durr; Francoise Pousset; Michael Parkinson; Robyn Labrum; Paola Giunti; Susan L. Perlman; Martin B. Delatycki; Marguerite V. Eva...
• Keywords: Frataxin; Compound heterozygosity; Heterozygote advantage

Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur 96% affected individuals reduce frataxin expression. Remaining are compound heterozygous for a expansion point/insertion/deletion mutation. We examined disease-causing mutations impact on structure/function clinical outcome FRDA.We compared information from 111 heterozygotes 131 with homozygous expansions. Frataxin were using structural modeling, stability analyses systematic literature review, categorized into four groups: (1) expansions, three heterozygote groups; (2) null (no produced); (3) moderate/strong impact; (4) minimal impact. Mean age onset presence cardiomyopathy diabetes mellitus regression analyses.Mutations hydrophobic core whereas surface residue interactions iron sulfur cluster assembly heme biosynthetic proteins. The group had significantly earlier increased mellitus, to group. There no significant differences mean between homozygotes groups.In heterozygotes, expression partially functional mutant delays reduces those non-expanded allele. This integrated analysis their correlation provide definitive resource investigating pathogenesis FRDA.