Human Molecular Genetics, Vol 6, 2099-2107, Copyright © 1997 by Oxford University Press
V Mak, KA Jarvi, J Zielenski, P Durie and LC Tsui
The 5-thymidine (5T) variant of the cystic fibrosis transmembrane
conductance regulator (CFTR) intron 8 polypyrimidine tract (IVS8-T tract)
is the most frequent CFTR gene alteration identified in men with congenital
bilateral absence of vas deferens (CBAVD). This alternative splicing
variant gives rise to two transcripts, one normal with exon 9 intact and
the other with in-frame deletion of exon 9. That CBAVD men usually have
none of the other clinical signs of classical cystic fibrosis (CF) suggests
less functional CFTR is produced in the reproductive tract than in other
CF-associated organs. Nasal epithelia and segments of vas deferens were
obtained from healthy, previously vasectomized men who presented for
vasectomy reversal. Quantitative RT- PCR was performed on these specimens,
with the region of CFTR cDNA spanning exon 9 amplified. For both nasal and
vasal tissues, a strong positive correlation was found between the length
of the IVS8-T tract and the proportion of mRNA with exon 9 intact. In
addition, within the same subject, a significantly higher level of
transcripts lacking exon 9 was found in vas deferens than nasal epithelia,
regardless of the IVS8-T genotype. These findings suggest that the splicing
of CFTR precursor mRNA is less efficient in vasal epithelia compared with
respiratory epithelia. Thus, differential splicing efficiency between the
various tissues which express CFTR provides one possible explanation for
the reproductive tract abnormalities observed in infertile men with CFTR
gene alterations but without other clinical manifestations of CF.
ARTICLES
Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens
Division of Urology, Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
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