The molecular basis of partial penetrance of splicing mutations in cystic fibrosis

Naama Rave-Harel, Eitan Kerem, Malka Nissim-Rafinia, Igal Madjar, Ran Goshen, Arie Augarten, Ayelet Rahat, Arye Hurwitz, Ariel Darvasi, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The splicing variant, 5T allele, in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was shown to be associated with partial penetrance of the clinical expression. This splicing variant leads to two possible transcripts: one normal and the other aberrantly spliced that lacks exon 9. The aim of this study was to analyze the molecular basis of the partial penetrance in individuals carrying the 5T allele. We analyzed the level of the correctly spliced RNA transcribed from the 5T allele in nasal and epididymal epithelium and correlated it with disease expression. Semiquantitative nondifferential reverse-transcriptase-PCR showed a considerable variability (6%-37%) in the total level of correctly spliced RNA transcribed from the 5T allele in nasal epithelium from 11 patients. A significant nonlinear correlation (r = .82, P = .002) between the level of the normal CFTR transcripts and the severity of lung disease was shown. No individuals with normal lung function and minimal or no lung disease (FEV1 >80% predicted) had <25% of normal transcripts, and individuals with < 15% of normal transcripts did not have FEV1 > 80%. The level of normal transcripts in epididymal epithelial cells from four infertile males with congenital bilateral absence of the vas deferens was low (6% -24%). In infertile males with normal lung function the level of correctly spliced transcripts in the nasal epithelium was higher than the level in the epididymal epithelium. These results indicate that there is variability in the efficiency of the splicing mechanism, among different individuals and between different organs of the same individual. This variability provides the molecular basis of the partial penetrance of cystic fibrosis disease in patients carrying the 5T allele.

Original languageEnglish
Pages (from-to)87-94
Number of pages8
JournalAmerican Journal of Human Genetics
Volume60
Issue number1
StatePublished - Jan 1997
Externally publishedYes

Fingerprint

Dive into the research topics of 'The molecular basis of partial penetrance of splicing mutations in cystic fibrosis'. Together they form a unique fingerprint.

Cite this