Mutations in theMCFD2 gene and a novel mutation in theLMAN1 gene in Indian families with combined deficiency of factor V and VIII

Abstract

Combined deficiency of factors V (FV) and factor VIII (FVIII) (F5F8D) is an autosomal recessive bleeding disorder caused by simultaneous moderate-to-mild decrease of both clotting proteins. Mutations in two components of the ER-Golgi intermediate compartment (ERGIC-53), i.e., lectin mannose binding protein (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2), have been found to be responsible for this dual deficiency in most of the cases reported in literature. Three Indian families with F5F8D were analyzed for the presence of mutations in their LMAN1 and MCFD2 genes. One of the three families showed the presence of a G to A substitution in exon 2 of the MCFD2 gene, whereas another family showed a nonsense mutation, i.e., G to T substitution, in exon 2 of the LMAN1 gene, the latter being a novel mutation not previously reported. The third family did not show mutations in either of the two genes, suggesting that a significant subset of F5F8D cases may be due to additional genes resulting in a similar phenotype. Am.

The sugar-binding ability of ERGIC-53 is enhanced by its interaction with MCFD2

“…Each mutation behaves as a null allele that abolishes protein expression. [48][49][50] Seven MCFD2 mutations have been identified in 10 families. 50 More recently, novel mutations in LMAN1 and MCFD2 have been identified in F5F8D patients, including evidence for regulatory mutations that abolish BLOOD, 15 FEBRUARY 2008 ⅐ VOLUME 111, NUMBER 4 For personal use only.…”

Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2

“…A total of 19 different mutations in the LMAN1 gene have been reported to date in 49 families, 2,15,16 all of which appear to be null mutations that abolish protein expression. Seven MCFD2 mutations have been identified in 10 families.…”

Genotype-phenotype correlation in combined deficiency of factor V and factor VIII

“…6 Data on FV and FVIII levels are available for a total of 46 patients with MCFD2 mutations and a total of 96 patients with LMAN1 mutations (Table 2-3). [2][3][4][5][6]11,[19][20][21][22][23][24][25][26][27] Figure 2 shows a comparison of FV and FVIII levels between patients with MCFD2 mutations and patients with LMAN1 mutations. We observed a small but statistically significant difference in the distribution of FV and FVIII levels between these 2 classes of patients, with lower levels for both factors in the patients with MCFD2 mutations compared with those with LMAN1 mutations (mean values of 9.6 vs 13.7 for FV [P Ͻ .001] and 10.0 vs 16.0 for FVIII [P Ͻ .001]).…”