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Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations.
Methods Mol Med. 2006; 126:197-216.MM

Abstract

Friedreich ataxia (FA) is an autosomal-recessive disease primarily characterized by progressive neurological disability. A significant proportion of patients also present with a hypertrophic cardiomyopathy, which may, in some cases, cause premature death. FA is caused by insufficient levels of the protein, frataxin, which is involved in mitochondrial iron metabolism. All patients carry at least one copy of an intronic GAA triplet-repeat expansion that interferes with frataxin transcription. Normal chromosomes contain up to 35 to 40 GAA triplets in an Alu sequence localized in the first intron of the frataxin gene; FA chromosomes carry from approx 70 to more than 1000 GAA triplets. The molecular diagnosis of FA is, therefore, based on the detection of this expansion, which is present in homozygosity in more than 95% of the cases. The remaining patients are heterozygous for the GAA expansion and carry a frataxin point mutation as the other pathogenic allele. The expanded GAA triplet repeat may be detected by polymerase chain reaction (PCR) amplification followed by agarose gel electrophoresis analysis. In our hands, carefully performed PCR testing, in particular, if fragment detection is enhanced by hybridization with a GAA oligonucleotide probe, is as effective in identifying patients and carriers as is Southern blot analysis of genomic DNA, and allows a more accurate sizing of the repeat. Furthermore, in the case of smaller expansions, the amplified fragment may be directly sequenced to identify very rare nonpathogenic variant repeats, such as GAAGGA. Sequence analysis of the five coding exons of the frataxin gene should be performed in clinically affected individuals who are heterozygous for an expanded GAA repeat to identify point mutations.

Authors+Show Affiliations

Service de Neurologie, Université Libre de Bruxelles Hôpital Erasme, Bruxelles, Belgium.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16930014

Citation

Pandolfo, Massimo. "Friedreich Ataxia: Detection of GAA Repeat Expansions and Frataxin Point Mutations." Methods in Molecular Medicine, vol. 126, 2006, pp. 197-216.
Pandolfo M. Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations. Methods Mol Med. 2006;126:197-216.
Pandolfo, M. (2006). Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations. Methods in Molecular Medicine, 126, 197-216.
Pandolfo M. Friedreich Ataxia: Detection of GAA Repeat Expansions and Frataxin Point Mutations. Methods Mol Med. 2006;126:197-216. PubMed PMID: 16930014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations. A1 - Pandolfo,Massimo, PY - 2006/8/26/pubmed PY - 2006/12/22/medline PY - 2006/8/26/entrez SP - 197 EP - 216 JF - Methods in molecular medicine JO - Methods Mol Med VL - 126 N2 - Friedreich ataxia (FA) is an autosomal-recessive disease primarily characterized by progressive neurological disability. A significant proportion of patients also present with a hypertrophic cardiomyopathy, which may, in some cases, cause premature death. FA is caused by insufficient levels of the protein, frataxin, which is involved in mitochondrial iron metabolism. All patients carry at least one copy of an intronic GAA triplet-repeat expansion that interferes with frataxin transcription. Normal chromosomes contain up to 35 to 40 GAA triplets in an Alu sequence localized in the first intron of the frataxin gene; FA chromosomes carry from approx 70 to more than 1000 GAA triplets. The molecular diagnosis of FA is, therefore, based on the detection of this expansion, which is present in homozygosity in more than 95% of the cases. The remaining patients are heterozygous for the GAA expansion and carry a frataxin point mutation as the other pathogenic allele. The expanded GAA triplet repeat may be detected by polymerase chain reaction (PCR) amplification followed by agarose gel electrophoresis analysis. In our hands, carefully performed PCR testing, in particular, if fragment detection is enhanced by hybridization with a GAA oligonucleotide probe, is as effective in identifying patients and carriers as is Southern blot analysis of genomic DNA, and allows a more accurate sizing of the repeat. Furthermore, in the case of smaller expansions, the amplified fragment may be directly sequenced to identify very rare nonpathogenic variant repeats, such as GAAGGA. Sequence analysis of the five coding exons of the frataxin gene should be performed in clinically affected individuals who are heterozygous for an expanded GAA repeat to identify point mutations. SN - 1543-1894 UR - https://www.unboundmedicine.com/medline/citation/16930014/Friedreich_ataxia:_Detection_of_GAA_repeat_expansions_and_frataxin_point_mutations_ L2 - http://www.diseaseinfosearch.org/result/2931 DB - PRIME DP - Unbound Medicine ER -