SPLICE-MEDIATED INSERTION OF AN ALU SEQUENCE IN THE COL4A3 MESSENGER-RNA CAUSING AUTOSOMAL RECESSIVE ALPORT SYNDROME

被引:94
作者
KNEBELMANN, B
FORESTIER, L
DROUOT, L
QUINONES, S
CHUET, C
BENESSY, F
SAUS, J
ANTIGNAC, C
机构
[1] UNIV PARIS 05,HOP NECKER ENFANTS MALAD,INSERM,U423,F-75743 PARIS 15,FRANCE
[2] UNIV PARIS 05,HOP NECKER ENFANTS MALAD,DEPT NEPHROL,F-75743 PARIS 15,FRANCE
[3] UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT ENVIRONM & COMMUNITY MED,PISCATAWAY,NJ 08854
[4] FDN VALENCIANA INVEST BIOMED,INST INVEST CITOL,E-46010 VALENCIA,SPAIN
[5] HOP ST PIERRE,DEPT NEPHROL,LA REUNION,FRANCE
关键词
D O I
10.1093/hmg/4.4.675
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alport syndrome is a mainly X-linked hereditary disease of basement membranes characterized by progressive renal failure, deafness, and ocular lesions. The alpha 3(1V) and alpha>4(IV) collagen genes have been recently shown to be involved in the less frequent autosomal recessive form. When screening lymphocyte COL4A3 mRNAs from Alport patients, we found a mutant whose transcripts were disrupted by a 74 bp insertion at the junction of exons IV or V and VI. The insertion derives from an antisense Alu element in COL4A3 intron V, which has been spliced into the alpha 3(IV) mRMA due to a G to T transversion activating a cryptic acceptor splice site in this Alu element. There is complete segregation of this mutation with the disease in the family. Our findings provide the first evidence for the pathogenic role of abnormal splicing of COL4A3. Moreover, we demonstrate the superiority of mutation screening at the mRNA level to detect a hitherto poorly recognized mutation mechanism in humans, splice-mediated insertion of an Alu fragment into a coding sequence.
引用
收藏
页码:675 / 679
页数:5
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