Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection.

摘要: Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GP(IIb)-IIIa (integrin alpha(IIb)beta3). A patient with GT was identified as homozygous for a G-->A mutation 6 bp upstream of GP(IIIa) exon 9 splice donor site. Patient transcripts lacked despite normal DNA sequence all cis-acting sequences known to regulate site selection. In vitro analysis generated mini-gene constructs demonstrated that skipping occurred only when cis polymorphism 116 upstream, providing precedence two variations same which do not alter consensus sites and generate missense or nonsense mutations, can affect The mutant transcript resulted utilization cryptic acceptor returned open reading frame. These data support hypothesis pre-mRNA secondary structure allelic variants influence splicing provide new insight into regulated control RNA processing. addition, haplotype suggested has identical copies chromosome 17. Markers studied on three other chromosomes this finding due consanguinity. restricted phenotype may information regarding expression potentially imprinted genes