Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency

Abstract

Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals. The aim of the present study was to screen for and analyse F13B gene defects in the German population. A total of 150 patients presenting with suspected FXIII deficiency and one patient with severe (homozygous) FXIII deficiency were screened for mutations in F13A and F13B genes. Twenty-five individuals presented with detectable heterozygous mutations, 12 of them in the F13A gene and 13 of them in the F13B gene. We report on the genotype-phenotype correlations of the individuals showing defects in the F13B gene. Direct sequencing revealed 12 unique mutations including seven missense mutations (Cys5Arg, Ile81Asn, Leu116Phe, Val217Ile, Cys316Phe, Val401Glu, Pro428Ser), two splice site mutations (IVS2-1G>C, IVS3-1G>C), two insertions (c.1155_1158dupACTT, c.1959insT) and one in-frame deletion (c.471-473delATT). Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358). Another three missense mutations, (Leu116Phe, Val401Glu, Pro428Ser) were located proximal to other cysteine disulphide bonds, therefore indicating that the region in and around these disulphide bonds is prone to functionally relevant mutations in the FXIII-B subunit. The present study reports on a fairly common prevalence of F13B gene defects in the German population. The regions in and around the cysteine disulphide bonds in the FXIII-B protein may be regions prone to frequent mutations.

The Non-catalytic B Subunit of Coagulation Factor XIII Accelerates Fibrin Cross-linking

“…In addition to the conservation of FXIII-A in blood, this accelerating effect of FXIII-B on Fbn cross-linking is expected to be responsible for maintaining hemostasis because FXIII-B deficiency results in an increased bleeding tendency despite having a milder phenotype than FXIII-A deficiency (11,36).…”

Novel aspects of factor XIII deficiency

“…It was shown in two parallel publications that a small insertion (c.869insC) is the dominant mutation in Tunisian FXIII-A-deficient patients, which is due to an ancient founder effect [21 ,22]. In addition to the five previously described mutations in the FXIII-B gene that led to homozygous or compound heterozygous FXIII-B deficiency, a new homozygous case with duplication in exon 7 (c.1155_1158dupACTT) was reported [23 ]. The mutation resulted in a protein lacking the last five sushi domains.…”

In VitroSecretion Deficits are Common Among Human Coagulation Factor XIII Subunit B Missense Mutants: Correlations with Patient Phenotypes and Molecular Models

“…Accordingly, FXIII deficiency is described by the following three‐tier classification system: (1) severe deficiency, undetectable FXIII activity associated with spontaneous major bleeding; (2) moderate deficiency, <30% FXIII activity associated with mild spontaneous or triggered bleeding; (3) mild deficiency, >30% FXIII activity associated with a mostly asymptomatic disease course. The majority of causative FXIII heterozygous or homozygous mutations affect the F13A1 gene [Biswas et al., ], but seven different heterozygous F13B gene mutations were recently discovered that are associated with heritable mild FXIII deficiency [Ivaskevicius et al., ]. Previously only five FXIIIB mutations, including only one missense mutation, were reported.…”