Download Trinucleotide repeats ataxia - Genetics in the 3rd millennium

Abstract book of 3rd Iranian annual neurogenetic congress
Trinucleotide repeats ataxia
Massoud Houshmand*, Shahriar Nafisi, Mohammad Heydari,
Sepideh Safaie, Omid Aryani, Akbar Soltanzadeh, Mehdi Shafa
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of
gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy
of the cerebellum occurs. The hereditary ataxias are categorized by and causative or chromosomal . Genetic
forms of ataxia must be distinguished from the many acquired (non-genetic) causes of ataxia. The genetic
forms of ataxia are diagnosed by, physical examination, and neuroimaging. Molecular genetic tests are available
for the diagnosis of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17, DRPLA, Friedreich
ataxia (FRDA), in Iran. Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide
repeats in certain genes exceeding the normal stable threshold which differs per gene. The mutation is a subset
of unstable microsatellite repeats that occurs throughout all genomic sequences. If the repeat is present in a
healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. Trinucleotide
repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide
expansion up to a repeat number above a certain threshold level. Trinucleotide repeat disorders generally show
genetic anticipation, where their severity increases with each successive generation that inherits them. In over
half of these disorders, the repeated codon is CAG and codes for glutamine (Q) resulting in a polyglutamine
tract. These diseases are commonly referred to as polyglutamine (or PolyQ) diseases. In the remaining disorders,
repeated codons do not code for glutamine and are classified as non-polyglutamine diseases. Friedreich's ataxia
(FRDA) is characterized by slowly progressive ataxia with a mean age of onset between 10 and 15 years and
usually before 25 years of age. FRDA is typically associated with dysarthria, muscle weakness, spasticity in
the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration
sense. Approximately two-thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes
mellitus, and approximately 25% have an "atypical" presentation as a later onset or retained tendon reflexes.
Individuals with FRDA have identifiable Mutation in the FXN. The most common type of , which is observed
on both alleles in more than 98% of individuals with FRDA, is a GAA triplet-repeat expansion in Mutation
1 of FXN. Approximately 2% of individuals with FRDA are compound heterozygotes for a GAA expansion
in a disease-causing range in one FXN allele and another inactivating FXN intron in the other allele. FRDA
is inherited in an autosomal recessive manner.
We studied 137 Iranian patients (50 females and 87 males) from 110 unrelated families. DNA from each patient
was extracted and frequency and length of (GAA)n repeat was analyzed using a long-range polymerase chain
reaction (PCR) test. Also, we investigated the impact of GAA size on neurological findings, age of onset and
disease development. Homozygous GAA expansion was found in 101 (73%) cases. In four cases (27%), no
expansion was observed, ruling out the diagnosis of Friedreich’s ataxia. We also found that a biochemical
defect in complex I activity and ATP production, which may be due to iron accumulation in mitochondria, can
be involved in age of onset of FRDA. We also showed the possibility of mutations in ND genes which could
constitute a predisposing factor which affects age of onset and disease progression in combination with
*Massoud Houshmand, Ph.D
Assist Prof of Molecular Genetic, National Institute for
Genetic Engineering and Biotechnology, Tehran, Iran
E.mail: [email protected]
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Abstract book of 3rd Iranian annual neurogenetic congress
environmental risk factors. Mitochondrial D-loop sequencing results showed that the rate of D-loop variations
was higher in FA patients than controls (P<0.05). MtDNA deletions were present in 76% of our patients
representing mtDNA damage which may be due to iron accumulation in mitochondria. Synonyms for ADCA
(Autosomal Dominant Cerebellar Ataxias) which were used prior to the identification of the molecular genetic
basis of these disorders were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy,
or the more generic term, spinocerebellar degeneration. The spinocerebellar ataxias (SCA) comprise a
heterogeneous group of severe late-onset neurodegenerative diseases that are promoted by the expansion of
a tandem-arrayed DNA sequence that modifies the primary structure of the protein. Analysis of SCA in 20
patients showed high levels of mtDNA variations in lymphocytes. It can be proposed that the SCA gene proteins
(Ataxins) are involved in the complicated intracellular mechanisms that affect cellular organelles and their
components, such as the mitochondrial genome. The instability of CAG repeats in polyglutamine diseases such
as SCAs and Huntington's disease might be a causative factor in mtDNA variation or possible damage.
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