Am. J. Respir. Crit. Care Med., Volume 159, Number 6, June 1999, 1998-2002

Variable Levels of Normal RNA in Different Fetal Organs Carrying a Cystic Fibrosis Transmembrane Conductance Regulator Splicing Mutation

ORNIT CHIBA-FALEK, RICHARD B. PARAD, EITAN KEREM, and BATSHEVA KEREM

Department of Genetics, The Hebrew University, Jerusalem; Department of Pediatrics and Cystic Fibrosis Center, Shaare Zedek Medical Center, Hebrew University Medical School, Jerusalem, Israel; and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

Disease severity varies among cystic fibrosis (CF) patients carrying the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype and among organs of the same individual. It has been shown that the class V splicing mutation 3849 + 10 kb C T produces both normal and aberrantly spliced CFTR transcripts. We analyzed the levels of normal CFTR messenger RNA (mRNA) in different organs of an aborted fetus carrying the 3849 + 10 kb C T mutation, and found that they correlated with the histopathologic changes observed in these organs. We performed semiquantitative nondifferential reverse transcription-polymerase chain reaction on several organs from a 22-wk aborted CF fetus carrying the 3849 + 10 kb C T mutation. A very low level (1%) of normal CFTR mRNA was detected in the severely affected ileum of this fetus. Higher levels were found in the histopathologically unaffected trachea (17%), colon (19%), and lung (26%). Thus, as early as in utero, the regulation of alternative splice-site selection is an important mechanism underlying variable CF severity. Understanding of the mechanisms regulating alternative splicing in different tissues will contribute to potential therapy for patients carrying splicing mutations in CF and other human disease genes.

This article has been cited by other articles:

				F Stanke, M Ballmann, I Bronsveld, T Dork, S Gallati, U Laabs, N Derichs, M Ritzka, H-G Posselt, H K Harms, et al. Diversity of the basic defect of homozygous CFTR mutation genotypes in humans J. Med. Genet., January 1, 2008; 45(1): 47 - 54. [Abstract] [Full Text] [PDF]

				R. Radpour, H. Gourabi, M. A. S. Gilani, and A. V. Dizaj Molecular Study of (TG)m(T)n Polymorphisms in Iranian Males With Congenital Bilateral Absence of the Vas Deferens J Androl, July 1, 2007; 28(4): 541 - 547. [Abstract] [Full Text] [PDF]

				I. Aznarez, E. M. Chan, J. Zielenski, B. J. Blencowe, and L.-C. Tsui Characterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene Hum. Mol. Genet., August 15, 2003; 12(16): 2031 - 2040. [Abstract] [Full Text] [PDF]

				F. Pagani, C. Stuani, M. Tzetis, E. Kanavakis, A. Efthymiadou, S. Doudounakis, T. Casals, and F. E. Baralle New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12 Hum. Mol. Genet., May 15, 2003; 12(10): 1111 - 1120. [Abstract] [Full Text] [PDF]

				M. Nissim-Rafinia, O. Chiba-Falek, G. Sharon, A. Boss, and B. Kerem Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations Hum. Mol. Genet., July 22, 2000; 9(12): 1771 - 1778. [Abstract] [Full Text] [PDF]