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

ABSTRACT: Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2.

SUBMITTER: Zhang B

PROVIDER: S-EPMC2424156 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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

Zhang Bin B Spreafico Marta M Zheng Chunlei C Yang Angela A Platzer Petra P Callaghan Michael U MU Avci Zekai Z Ozbek Namik N Mahlangu Johnny J Haw Tabitha T Kaufman Randal J RJ Marchant Kandice K Tuddenham Edward G D EG Seligsohn Uri U Peyvandi Flora F Ginsburg David D

Blood 20080407 12

Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with ...[more]

PMID: 18391077

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Project description:BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency are variable.ObjectiveThis study aimed to characterize the genotype-phenotype correlation of G6PD mutations in Thai pediatric patients who were followed-up in Phramongkutklao Hospital, a tertiary center in central Thailand. Material and Method. A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of all coding exons of the G6PD gene. Ninety-one patients (89.2%) were presented with neonatal hyperbilirubinemia and 11 patients (10.8%) were presented with acute hemolytic anemia beyond the neonatal period.ResultsMolecular analysis of the G6PD gene in 102 G6PD-deficient Thai children identified 12 different mutations. G6PD Viangchan (871G > A) and G6PD Canton (1376G > T) were the first (46.2%) and the second (15.4%) most common identified mutations among both male and female G6PD-deficient individuals, respectively. All affected males were hemizygous for G6PD mutations and had an average G6PD level of 16.7 ± 11.5 (3-76) IU/ml.RBC. Majority of female patients (27 in 29, 93.1%) were heterozygous for G6PD mutations and had an average G6PD level of 133.6 ± 43.4 (9-195) IU/ml.RBC. Two female patients (6.9%) were either homozygous or compound heterozygous for the mutations and had G6PD level in the affected male range (35 and 10 IU/ml.RBC). Only 1 in 27 heterozygous females (3.7%) had G6PD level in the affected male range (9 IU/ml.RBC) which is possibly explained by nonrandom X-chromosome inactivation. The correlation of genotypes, G6PD levels, and clinical phenotypes was not demonstrated in our study in which all of the included G6PD-deficient patients were presented with neonatal hyperbilirubinemia and acute hemolytic anemia, since the genotype-phenotype correlation is normally demonstrated in chronic nonspherocytic hemolytic anemia (CNSHA) G6PD-deficient individuals.ConclusionThis study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify 12 missense mutations in Thai children.

Project description:BACKGROUND:Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in I?B? that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor ? light chain enhancer of activated B cells (NF-?B) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in I?B? have impaired noncanonical NF-?B activity and defective lymphorganogenesis. OBJECTIVE:We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS:A disease severity scoring system was devised. Stability of I?B? mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-?B signaling in skin-derived fibroblasts. RESULTS:Disease severity was greater in patients with I?B? point mutations than in those with truncation mutations. I?B? point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-?B-dependent IL-6 secretion and upregulation of the NF-?B subunit 2/p100 and RELB proto-oncogene, NF-?B subunit (RelB) components of the noncanonical NF-?B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-?B-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus ?-lymphotoxin ? receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS:I?B? point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-?B activity in patients with AD EDA-ID.

Dataset Information

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

Publications

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

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