Friedreich ataxia (FRDA)
2008/4.20/
Neurogenetics. 2007 Nov;8(4):289-99.
Epub 2007 Aug 17. Gellera C, Castellotti B, Mariotti C, Mineri R, Seveso V, Didonato S, Taroni F. UO Biochimica e Genetica, Fondazione IRCCS Istituto Neurologico "Carlo Besta",
via Celoria 11, 20133 Friedreich
ataxia (FRDA) is associated with a GAA-trinucleotide-repeat
expansion in the first intron of the FXN gene
(9q13-21), which encodes a 210-amino-acid protein named frataxin.
More than 95% of patients are homozygous for 90-1,300 repeat expansion on
both alleles. The remaining patients have been shown to be compound
heterozygous for a GAA expansion on one allele and a micromutation
on the other. The reduction of both frataxin
messenger RNA (mRNA) and protein was found to be proportional to the size
of the smaller GAA repeat allele. We report a clinical and molecular study
of 12 families in which classical FRDA patients were heterozygous for a GAA
expansion on one allele. Sequence analysis of the FXN gene allowed the
identification of the second disease-causing mutation in each heterozygous
patient, which makes this the second largest series of FRDA compound heterozygotes reported thus far. We have identified
seven mutations, four of which are novel. Five patients carried missense mutations, whereas eight patients carried null
(frameshift or nonsense) mutations. Quantitation of frataxin
levels in lymphoblastoid cell lines derived from
six compound heterozygous patients showed a statistically significant
correlation of residual protein levels with the age at onset (r = 0.82, p
< 0.05) or the GAA expansion (r = -0.76, p < 0.1). In the group of
patients heterozygous for a null allele, a strong (r = -0.94, p < 0.01)
correlation was observed between the size of GAA expansion and the age at
onset, thus lending support to the hypothesis that the residual function of
frataxin in patients' cells derive exclusively
from the expanded allele. PMID: 17703324 [PubMed
- indexed for MEDLINE] Ann Neurol. 2007 Jan;61(1):55-60. De
Biase I, Rasmussen
A, Endres D, Al-Mahdawi
S, Monticelli A, Cocozza S, Pook M, Bidichandani SI. Department
of Biochemistry and Molecular Biology, OBJECTIVE: Friedreich's
ataxia patients are homozygous for expanded alleles of a GAA triplet-repeat
sequence in the FXN gene. Patients develop progressive ataxia due to
primary neurodegeneration involving the dorsal
root ganglia (DRGs). The selective neurodegeneration is due to the sensitivity of DRGs to frataxin deficiency;
however, the progressive nature of the disease remains unexplained. Our
objective was to test whether the expanded GAA triplet-repeat sequence
undergoes further expansion in DRGs as a possible
mechanism underlying the progressive pathology seen in patients. METHODS:
Small-pool polymerase chain reaction analysis, a sensitive technique that
allows the measurement of repeat length in individual FXN genes, was used
to analyze somatic instability of the expanded GAA triplet-repeat sequence
in multiple tissues obtained from six autopsies of Friedreich's
ataxia patients. RESULTS: DRGs showed a
significantly greater frequency of large expansions (p < 0.001) and a
relative paucity of large contractions compared with all other tissues.
There was a significant age-dependent increase in the frequency of large
expansions in DRGs, which ranged from 0.5% at 17
years to 13.9% at 47 years (r = 0.78; p = 0.028). INTERPRETATION:
Progressive pathology involving the DRGs is
likely due to age-dependent accumulation of large expansions of the GAA triplet-repeat
sequence. Thus, somatic instability of the expanded GAA triplet-repeat
sequence may contribute directly to disease pathogenesis and progression.
Progressive repeat expansion in specific tissues is a common theme in the
pathogenesis of triplet-repeat diseases. PMID: 17262846 [PubMed
- indexed for MEDLINE] 1: Hum Genet.
2007 Jan;120(5):633-40. Epub
2006 Sep 21. Clark
RM, De
Biase I, Malykhina AP, Al-Mahdawi S, Pook M, Bidichandani SI. Department
of Biochemistry and Molecular Biology, Friedreich
ataxia (FRDA) is caused by homozygosity for FXN
alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence.
Patients have progressive neurodegeneration of
the dorsal root ganglia (DRG) and in later stages the cerebellum may be
involved. The expanded GAA-TR sequence is unstable in somatic cells in
vivo, and although the mechanism of instability remains unknown, we
hypothesized that age-dependent and tissue-specific somatic instability may
be a determinant of the progressive pathology involving DRG and cerebellum.
We show that transgenic mice containing the expanded GAA-TR sequence (190
or 82 triplets) in the context of the human FXN locus show tissue-specific
and age-dependent somatic instability that is compatible with this
hypothesis. Small pool PCR analysis, which allows quantitative analysis of
repeat instability by assaying individual transgenes
in vivo, showed age-dependent expansions specifically in the cerebellum and
DRG. The (GAA)(190) allele showed some instability by 2 months, progressed
at about 0.3-0.4 triplets per week, resulting in a significant number of
expansions by 12 months. Repeat length was found to determine the age of
onset of somatic instability, and the rate and magnitude of mutation. Given
the low level of cerebellar instability seen by
others in multiple transgenic mice with expanded CAG/CTG repeats, our data
indicate that somatic instability of the GAA-TR sequence is likely mediated
by unique tissue-specific factors. This mouse model will serve as a useful
tool to delineate the mechanism(s) of disease-specific somatic instability
in FRDA. PMID: 17024371 [PubMed
- indexed for MEDLINE]
Frataxin gene point mutations in Italian Friedreich
ataxia patients.
Progressive GAA expansions
in dorsal root ganglia of Friedreich's ataxia
patients.
The GAA triplet-repeat is unstable in the
context of the human FXN locus and displays age-dependent expansions in
cerebellum and DRG in a transgenic mouse model.