Fibroblast phenotype in male carriers of FMR1 premutation alleles.
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.
Garcia-Arocena
Dolores
D
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95616, USA.
Yang
Jane E
JE
Brouwer
Judith R
JR
Tassone
Flora
F
Iwahashi
Christine
C
Berry-Kravis
Elizabeth M
EM
Goetz
Christopher G
CG
Sumis
Allison M
AM
Zhou
Lili
L
Nguyen
Danh V
DV
Campos
Luis
L
Howell
Erin
E
Ludwig
Anna
A
Greco
Claudia
C
Willemsen
Rob
R
Hagerman
Randi J
RJ
Hagerman
Paul J
PJ
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
D051860:Fragile X Messenger Ribonucleoprotein 1; D034882:Lamins; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse