Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema

Donatella Frangi, Marco Cicardi, Antonio Sica, Francesco Colotta, Angelo Agostoni, Alvin E. Davis

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Members of two unrelated families with type I hereditary angiooeurotic edema (HANE) were found to have elevated levels of C1 inhibitor (C1INH) mRNA. DNA sequence analysis of PCR-amplified monocyte C1INH mRNA revealed normal and mutant transcripts, as expected in this disorder that occurs in heterozygous individuals. Single base mutations near the 3′ end of the coding sequence were identified in affected members of each family. One mutation consisted of insertion of an adenosine at position 1304 which created a premature termination codon (TAA), whereas the second consisted of deletion of the thymidine at position 1298 which created a premature termination codon (TGA) 23 nucleotides downstream. These mutations are ∼ 250 nucleotides upstream of the natural termination codon. Nuclear run-off experiments in one kindred revealed no difference in transcription rates of the C1INH gene between the patients and normals. C1INH mRNA half-life experiments were not technically feasible because of the prolonged half-life of the normal transcript. Dideoxynucleotide primer extension experiments allowed the differentiation of the normal and mutant transcripts. These studies showed that the mutant transcript nas not decreased relative to the normal, and this therefore was at least partially responsible for the C1INH mRNA elevation. This elevation may be due to the decreased catabolism of the mutant transcript.

Lingua originaleInglese
pagine (da-a)755-759
Numero di pagine5
RivistaJournal of Clinical Investigation
Volume88
Numero di pubblicazione3
Stato di pubblicazionePubblicato - set 1991
Pubblicato esternamente

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