title: Homozygous intronic mutation leading to inefficient transcription combined with a novel frameshift mutation in F13A1 gene causes FXIII deficiency.
abstract: Two novel mutations, 602-605delAAAG in exon 5 and Int1(+12)C>A, of the F13A1 gene were identified in a Chinese factor XIII (FXIII)-deficient family. The 602-605delAAAG mutation results in the premature termination of translation. To determine the functional effect of the Int1(+12)A mutation, we transiently expressed luciferase reporters in U937 cells. We found that the first 951 bp of F13A1 intron 1 is involved in regulating the expression of the F13A1 gene and that Int1(+12)A results in its reduced expression. Electrophoretic mobility shift assay indicated that Int1(+12)A causes reduced protein binding. An Sp1 site was predicted in the sequence containing Int1(+12)C, which the Int1(+12)A mutation eliminates. Co-transfection of a plasmid expressing Sp1 revealed that Sp1 is involved in regulating the expression of FXIIIA and that Int1(+12)A leads to inefficient transcription. These results provide the first insight into a novel regulatory mechanism involving intron 1 in the F13A1 gene.
authors.affiliation: Department of Biochemistry, Hainan Medical College, Haikou, Hainan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lijun
authors.initials: L
authors.lastname: Huang
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Ma
authors.forename: Deqian
authors.initials: D
authors.lastname: Xiao
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Chen
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Keyuan
authors.initials: K
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Man
authors.initials: M
authors.lastname: Xiao
authors.forename: Guankui
authors.initials: G
authors.lastname: Du
authors.forename: Xinbao
authors.initials: X
authors.lastname: Hao
authors.forename: Wangwei
authors.initials: W
authors.lastname: Cai
mesh_terms: D000328:Adult; D001483:Base Sequence; D005177:Factor XIII Deficiency / Q000097:blood / Q000235:genetics*; D026122:Factor XIIIa / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005786:Gene Expression Regulation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D020298:U937 Cells
chemical_list: D026122:Factor XIIIa