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.
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95616, USA.
Dolores
D
Garcia-Arocena
Jane E
JE
Yang
Judith R
JR
Brouwer
Flora
F
Tassone
Christine
C
Iwahashi
Elizabeth M
EM
Berry-Kravis
Christopher G
CG
Goetz
Allison M
AM
Sumis
Lili
L
Zhou
Danh V
DV
Nguyen
Luis
L
Campos
Erin
E
Howell
Anna
A
Ludwig
Claudia
C
Greco
Rob
R
Willemsen
Randi J
RJ
Hagerman
Paul J
PJ
Hagerman
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