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A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter

DE GOBBI, Marco;
2006-01-01
2006
Inglese
WOS:000237957400054
2-s2.0-33744475085
SCIENCE
312
1215
1217
We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder a thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a. combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of at[ downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.
GLOBIN GENES; HUMAN GENOME; CLUSTER; REGION; POLYMORPHISMS; ACTIVATION; SEQUENCES; COMPLEX; GATA-1; ZETA
262
15
M. De Gobbi;V. Viprakisit;J. R. Hughes;C. Fisher;V. J. Buckle;H. Ayyub;R. J. Gibbons;D. Vernimmen;Y. Yoshinaga;P. d. Jong;J. F. Cheng;E. M....espandi
info:eu-repo/semantics/article
none
03-CONTRIBUTO IN RIVISTA::03A-Articolo su Rivista
03A-Articolo su Rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/93291
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