BAK, BAX, and NBK/BIK proapoptotic gene alterations in Iranian patients with ataxia telangiectasia.
BACKGROUND
Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder characterized by variable immunodeficiency, progressive neurodegeneration, occulocutaneous telangiectasia, and an increased susceptibility to malignancies. This study was designed to study the role of proapoptotic BAK, BAX, and NBK/BIK genes in a group of patients with AT to elucidate the possible role of these genes in progression of malignancies in this disease.


METHODS
Fifty Iranian patients with AT were investigated in this study. The entire coding regions of the BAK gene (exons 2-6), NBK/BIK gene (exons 2-5), and BAX gene (exons 1-7) were amplified using polymerase chain reaction (PCR). The PCR products were separated by 2% agarose gel electrophoresis, and all positive samples were verified by direct sequencing of PCR products using the same primers used for PCR amplification, BigDye chemistry, and Avent 3100 Genetic Analyzer following the manufacturer's instructions (Applied Biosystems).


RESULTS
Eight of fifty Iranian AT patients (16%) exhibited a C > T transition in exon 2 (c342C > T) of the BAK gene, while none of the healthy controls had such alteration (P = 0.0001). Higher frequency of another nucleotide substitution in the noncoding region of exon 7 in BAX gene (6855G > A) was also identified in 68% of the patient group versus 24% in the controls (P < 0.0001). Sequence alteration in intronic region of the NBK/BIK gene IVS4-12delTC was observed in 52% of AT patients, which was significantly higher than 20% in the control group (P = 0.0023). Another variant IVS1146C > T in the intronic region of the BAX gene was found in 78% of patients, which was significantly higher than 10% in the controls (P < 0.0001). Frequency of alteration in intronic region of exon 3 of the BAX gene (IVS3 + 14A > G) was also significantly higher in the AT patients (P < 0.0001).


CONCLUSIONS
Several alterations in the proapoptotic genes BAK, NBK/BIK, and BAX were found in our study, which could elucidate involvement of the mitochondrial pathway mediated apoptosis in accelerating and developing of cancers and in immunopathogenesis of AT. Such altered apoptosis in AT could play some roles in developing cancers in this group of patients.
Isaian
Anna
A
National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. isaiian@sina.tums.ac.ir
Bogdanova
Natalia V
NV
Houshmand
Masoud
M
Movahadi
Masoud
M
Aghamohammadi
Asghar
A
Agamohammadi
Asghar
A
Rezaei
Nima
N
Atarod
Lida
L
Sadeghi-Shabestari
Mahnaz
M
Tonekaboni
Seyed Hasan
SH
Chavoshzadeh
Zahra
Z
Hassani
Seyed Mohammad Seyed
SM
Mirfakhrai
Reza
R
Cheraghi
Taher
T
Kalantari
Najmoddin
N
Ataei
Mitra
M
Dork-Bousset
Thilo
T
Sanati
Mohammad Hossein
MH
D000293:Adolescent; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000276:immunology; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D047668:Inteins / Q000235:genetics; D007492:Iran; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D024101:Mitochondrial Proteins; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein