An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene.

Abstract

Friedreich's ataxia is the most common hereditary ataxia and is frequently associated with disturbances of glucose metabolism. This autosomal recessive disease is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene. Homozygous expansion of a GAA repeat in the first intron of X25 inhibits frataxin expression and is associated with clinical disease. We evaluated whether heterozygous expansions of the triplet repeat in the frataxin gene X25 may be associated with NIDDM in two genetically distinct populations--one in Germany (n = 358) and the other in the U.S. (n = 292)--using a polymerase chain reaction-based assay. Intermediate expansions (10-36 repeats), which are longer than normal but not sufficient for the appearance of the ataxia phenotype, were found in 24.7 and 27.3% of these two NIDDM cohorts compared with 7.6 and 6.3% of the matched control subjects (both P < 0.001). The odds ratios were 3.36 (95% CI 1.72-6.55) for the German group and 4.01 (2.08-7.74) for the U.S. group. Therefore, we conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore described. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

“…Nondiabetic FA patients exhibit normal basal insulin oscillations (M. Ristow et al, unpublished observations) and normal glucose-stimulated insulin secretion (13) but show some degree of insulin resistance (14,15). While studies on a possible association between the common type 2 diabetes and the frataxin GAA triplet repeat expansions in humans are inconclusive (16)(17)(18)(19)(20)(21), linkage of type 2 diabetes with the locus harboring the human frataxin gene at 9q13 was found in at least four different populations worldwide (22)(23)(24)(25), suggesting a role in the pathogenesis of common type 2 diabetes.…”

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

“…This observation is supported by previous studies that have clearly indicated an increased incidence of diabetes in FA-patients (17,18) together with normal or sometimes increased stimulus-coupled insulin secretion in FA-patients (19)(20)(21)(22) and obligate heterozygous carriers (18,22) of the GAA-tract expansion (i.e., >50 GAA repeats). On the other hand, population-based studies on premutations (i.e., >15 but <51 GAA repeats) and their association with common type 2 diabetes are as inconclusive (23)(24)(25)(26) as studies on the relevance of these premutations on transcription of the -based insulin sensitivity test (Y-axis, linear scale). Control subjects are represented by ᭺, whereas subjects with a heterozygous GAA expansion are represented by .…”

Sakharnyy diabet pri ataksii Fridreykha

“…Взгляд на АФ как на митохондриальную болезнь может открыть новые подходы к терапии этого за болевания. Появились данные о том, что экспансия ГАА-по-второв порядка 30-60 (длиннее нормальной), но недостаточная для проявления фенотипа АФ, чаще ассоциируется с СД, чем другие известные мутации [26]; однако ряд исследователей не поддерживает это мнение [11]. Дальнейшие исследования должны пролить свет на роль фратаксина в патогенезе СД.…”