Human Molecular Genetics Advance Access first published online on October 28, 2009
This version [Corrected Proof] published online on November 11, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp497
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Fibroblast phenotype in male carriers of FMR1 premutation alleles
1 Department of Biochemistry and Molecular Medicine and 2 Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California, Davis, CA, USA, 3 CBG-Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands, 4 M.I.N.D. Institute, 5 Department of Pathology and 6 Department of Pediatrics, University of California, Davis, Health System, Sacramento, CA, USA, 7 Departments of Pediatrics, Neurological Sciences, and Biochemistry, 8 Departments of Neurological Sciences and Pharmacology and 9 Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA 95616, USA. Tel: +1 5307547266; Fax: +1 5307547269; Email: pjhagerman{at}ucdavis.edu
Received June 16, 2009; Accepted October 26, 2009
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.