Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia

Gene Therapy ◽  
2016 ◽  
Vol 24 (5) ◽  
pp. 265-274 ◽  
Author(s):  
D L Ouellet ◽  
K Cherif ◽  
J Rousseau ◽  
J P Tremblay
Keyword(s):  
Mouse Models ◽  
Friedreich Ataxia ◽  
Gaa Repeats ◽  
Frataxin Gene

scholarly journals The Spectrum of Left Ventricular Changes in Friedreich Ataxia—Relation to Age and GAA Repeats in the Frataxin Gene

2012 ◽  
Vol 21 ◽  
pp. S273
Author(s):  
G. Romanelli ◽  
M. Delatycki ◽  
L. Donelan ◽  
R. Hassam ◽  
L. Corben ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Left Ventricular ◽  
Gaa Repeats ◽  
Frataxin Gene

scholarly journals Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4085
Author(s):  
Antonella Bizzoca ◽  
Martina Caracciolo ◽  
Patrizia Corsi ◽  
Thea Magrone ◽  
Emilio Jirillo ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Mitochondrial Protein ◽  
Growth Control ◽  
Epigallocatechin Gallate ◽  
Neurite Growth ◽  
Mutant Mice ◽  
Protective Effects ◽  
Protein Markers ◽  
Gaa Repeats ◽  
Frataxin Gene

In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

scholarly journals 321. Deletion of Mutated GAA Repeats from the Intron 1 of the Frataxin Gene Using the CRISPR System Restores the Protein Expression in a Friedreich Ataxia Model

2016 ◽  
Vol 24 ◽  
pp. S129
Author(s):  
Dominique L. Ouellet ◽  
Joel Rousseau ◽  
Khadija Cherif ◽  
Catherine Gérard ◽  
Renald Gilbert ◽  
...  
Keyword(s):  
Protein Expression ◽  
Friedreich Ataxia ◽  
Crispr System ◽  
Intron 1 ◽  
Gaa Repeats ◽  
Frataxin Gene

Frataxin gene point mutations in Italian Friedreich ataxia patients

Neurogenetics ◽  
2007 ◽  
Vol 8 (4) ◽  
pp. 289-299 ◽  
Author(s):  
Cinzia Gellera ◽  
Barbara Castellotti ◽  
Caterina Mariotti ◽  
Rossana Mineri ◽  
Viviana Seveso ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Point Mutations ◽  
Frataxin Gene

Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling

2016 ◽  
Vol 57 (3) ◽  
pp. 349-355 ◽  
Author(s):  
Dorota Hoffman-Zacharska ◽  
Tomasz Mazurczak ◽  
Tomasz Zajkowski ◽  
Renata Tataj ◽  
Paulina Górka-Skoczylas ◽  
...  
Keyword(s):  
Friedreich Ataxia ◽  
Molecular Testing ◽  
Gaa Repeats

scholarly journals Molecular Analysis of Friedreich's Ataxia in Macedonian Patients

2008 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
S Kocheva ◽  
S Trivodalieva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Molecular Analysis ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Autosomal Recessive Inheritance ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
The Republic ◽  
Gaa Repeats ◽  
Frataxin Gene

Molecular Analysis of Friedreich's Ataxia in Macedonian PatientsFriedreich's ataxia (FRDA) is rare a progressive neurodegenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spinocerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frataxin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.

scholarly journals Malaysian Siblings with Friedreich Ataxia and Chorea: A Novel Deletion in the Frataxin Gene

2004 ◽  
Vol 31 (3) ◽  
pp. 383-386 ◽  
Author(s):  
Siân D. Spacey ◽  
Blazej I. Szczygielski ◽  
Sean P. Young ◽  
Juliette Hukin ◽  
Kathy Selby ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Middle Eastern ◽  
Friedreich Ataxia ◽  
Hospital Setting ◽  
Southeast Asian ◽  
The Other ◽  
University Hospital ◽  
Compound Heterozygotes ◽  
Gaa Expansion ◽  
Frataxin Gene

Background:Friedrich ataxia (FRDA1) is most often the result of a homozygous GAA repeat expansion in the first intron of the frataxin gene (FRDA gene). This condition is seen in individuals of European, North African, Middle Eastern and Indian descent and has not been reported in Southeast Asian populations. Approximately 4% of FRDA1 patients are compound heterozygotes. These patients have a GAA expansion on one allele and a point mutation on the other and have been reported to have an atypical phenotype.Objective:To describe a novel dinucleotide deletion in the FRDA gene in two Malaysian siblings with FRDA1.Setting:Tertiary referral university hospital setting. Patients andMethods:A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period. His neurological exam revealed evidence of dysarthria and ataxia, mild generalized weakness and choreoform movements of the tongue and hands. His reflexes were absent and Babinski sign was present bilaterally. A nine-year-old sister was found to have mild ataxia but was otherwise neurologically intact.Results:Molecular genetic studies demonstrated that both siblings were compound heterozygotes with a GAA expansion on one allele and a novel dinucleotide deletion on the other allele.Conclusion:We describe a novel dinucleotide deletion in the first exon of the FRDA gene in two siblings with FRDA1. Additionally this is the first report of FRDA1 occurring in a family of southeast Asian descent, it demonstrates intrafamilial phenotypic variability, and confirms that atypical phenotypes are associated with compound heterozygosity.

Somatic Expansion of the Frataxin Gene GAA Repeats in MDS Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1642-1642
Author(s):  
Drorit Merkel ◽  
H. Joachim Deeg ◽  
Amos Simon ◽  
Ninette Amariglio ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Protein ◽  
Short Length ◽  
Mrna Levels ◽  
Normal Range ◽  
Heme Synthesis ◽  
Pcr Products ◽  
Gaa Repeats ◽  
The Impact ◽  
Frataxin Gene

Abstract The mitochondria play an important role in both apoptosis and heme synthesis. In patients with Myelodysplastic syndrome (MDS) the marrow is characterized by defective hematopoiesis, increased apoptosis and the presence of iron laden mitochondria. The molecular mechanisms responsible for increased apoptosis remain incompletely understood. Frederic’s ataxia (FRDA), the most common inherited ataxia, is a severe autosomal-recessive disease characterized by neurodegeneration, cardiomyopathy and diabetes, resulting from reduced synthesis of the mitochondrial protein frataxin which is involved in mitochondrial energy production and other cellular functions by providing iron for heme synthesis and iron–sulfur cluster (ISC) assembly and repair, serving as a Fe (II) donor for ferrochelatase. The underlying mutation consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene. Long expansions of a GAA tri-nucleotide in FRDA patients range from 66 to more than 1,700 repeats, whereas the normal range of repeats varies from 7 to 36. Abnormal expansion results in reduced frataxin mRNA levels, leading to reduced function of the respiratory chain. The aim of the present study was to determine if frataxin gene mutations occurred in MDS patients. We analyzed DNA from peripheral blood (PB) of 29 MDS patients and from 22 healthy marrow (BM) donors using repeat-Primed PCR. We also sampled genomic DNA products from buccal smears of the MDS patients. In MDS patients PCR of PB in 9 out of 24 patients (37%) showed short length (2–8 repeats), whereas PB of the remaining 15 patients (62.5%) showed longer PCR products (10–43 repeats, still in the “normal” range for FRDA). The PCR products of the buccal smears from all 14 patient samples were short (2–7 repeats), including those from 9 patients who had longer repeats in PB. In healthy BM donors, PCR of PB detected short length repeats (4–5 repeats) in17 of 20 individuals (85%), whereas 3 samples (15%) had longer PCR products (11–26 repeats). This was statistically significantly different from patients with MDS (P= 0.0014). The results indicate that MDS patients exhibit longer frataxin gene products than healthy individuals in PB, but not in buccal DNA. These data suggest a somatic mutation in the frataxin gene in hematopoetic cells of patients with MDS. Further studies will explore the impact of this mutation on mitochondrial function and on the pathophysiology of MDS.

scholarly journals Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e107416 ◽  
Author(s):  
Sara Anjomani Virmouni ◽  
Chiranjeevi Sandi ◽  
Sahar Al-Mahdawi ◽  
Mark A. Pook
Keyword(s):  
Transgenic Mouse ◽  
Mouse Models ◽  
Friedreich Ataxia ◽  
Transgenic Mouse Models ◽  
Functional Characterisation
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