Homozygous intronic mutation leading to inefficient transcription combined with a novel frameshift mutation in F13A1 gene causes FXIII deficiency

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. Journal of Human Genetics (2011) 56, 460-463; doi:10.1038/jhg.2011.41; published online 21 April 2011