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

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.