Detection of two Alu insertions in the CFTR gene.
BACKGROUND
LINE-1 (long interspersed element-1) or L1-mediated retrotransposition is a potent force in human genome evolution and an occasional cause of human genetic disease. Since the first report of two de novo L1 insertions in the F8 gene causing hemophilia A, more than 50 L1-mediated retrotranspositional events have been identified as causing human genetic disease. However, a significant bias has generally militated against the detection of these pathological events at autosomal loci. Based upon this and other observations, we surmised that some previously unresolved cystic fibrosis chromosomes might carry hitherto undetected L1-mediated retrotranspositional insertions at the CFTR locus. This study represents an attempt to identify such mutational events.


METHODS
100 previously unresolved cystic fibrosis chromosomes were carefully reanalyzed using quantitative high-performance liquid chromatography (QHPLC).


RESULTS
Two simple Alu insertions were identified in the CFTR gene, within exons 16 and 17b respectively.


CONCLUSIONS
Our findings have not only revealed a previously unknown mutational mechanism responsible for cystic fibrosis but also represent an important addition to the already diverse spectrum of known CFTR gene mutations. Experience with the CFTR gene suggests that pathological L1-mediated retrotranspositional events may also have been overlooked at other gene loci and should always be considered in cases that appear to be refractory to analysis.
Chen
Jian-Min
JM
INSERM, U613, 29220 Brest, France. Jian-Min.Chen@univ-brest.fr
Masson
Emmanuelle
E
Macek
Milan
M
Raguénès
Odile
O
Piskackova
Tereza
T
Fercot
Brigitte
B
Fila
Libor
L
Cooper
David N
DN
Audrézet
Marie-Pierre
MP
Férec
Claude
C
D020087:Alu Elements / Q000235:genetics*; D001483:Base Sequence; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator