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Molecular Study of (TG)_m(T)_n Polymorphisms in Iranian Males With Congenital Bilateral Absence of the Vas Deferens

MOHAMAD ALI SADIGHI GILANI

AHMAD VOSOUGH DIZAJ

From the ^* Department of Reproductive Genetics and Department of Male Infertility, Reproductive Biomedicine Research Center of Royan Institute, Tehran, Iran

Correspondence to: Ramin Radpour, Department of Reproductive Genetics, Reproductive Biomedicine Research Center of Royan Institute, PO Box 19395-4644, Tehran, Iran (e-mail: rradpour{at}royaninstitute.org).

Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia. Nearly 75% of men with CBAVD have at least 1 detectable common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The different alleles at the (TG)_m(T)_n polymorphic locus at the 3' end of human CFTR intron 8 determine the efficiency of exon 9 splicing. To study the CFTR gene mutations and (TG)_m(T)_n polymorphisms in Iranian CBAVD patients with presumed low CF frequency and to better understand the complex regulation of exon 9 splicing among our study population, we analyzed CFTR mutations and (TG)_m(T)_n polymorphisms in 112 Iranian CBAVD, 7 congenital unilateral absence of the vas deferens males from Iran, and 84 fertile males as controls. Moreover, we compared the rate of CFTR transcripts with exon 9 (9+) with reduction of the (T)_n repeat in our study population. Our study showed that the 5T mutation was present with high frequency in our patients. Longer (TG)_m polymorphic tracts increase the proportion of exon 9 deletion transcripts but only when activated by the 5T allele. The combination of the 5T allele in 1 copy of the CFTR gene with a CF mutation in the other copy is the most common cause of CBAVD in the Iranian population. We also observed the highest level of exon 9+ splicing efficiency among the tested samples with the (TG)₁₂(T)₇ allele, which represents the most common intron 8 splice variant allele in the general population. Our results support the idea that a putative role of the (T)_n repeat is to distance the (TG)_m repeat from the 3' splice site and that the different alleles at the (T)_n locus affect the efficiency by which the splice acceptor consensus sequence is recognized.

     Key words: CBAVD, CFTR, IVS8-5T, male infertility

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