title: Mutations in the MCFD2 gene are predominant among patients with hereditary combined FV and FVIII deficiency (F5F8D) in India.
abstract: Combined FV and FVIII deficiency (F5F8D) is a rare (1:1.000.000) autosomal recessive disorder caused by a defect in the LMAN1 or MCFD2 genes, encoding for a FV and FVIII cargo receptor complex. We report the phenotype and genotype analyses in nine unrelated Indian patients with low FV and FVIII coagulant activity [FV:C, range: 5.6-22.4% and FVIII:C, range: 8.3-27.1%]. Four homozygous mutations, including two frame shift, one missense and one splice site, were identified in all the nine patients. Three of them, a 72-bp deletion in LMAN1 (c.813_822 + 62del72, p.K272fs), a 35-bp deletion in MCFD2 (c.210_244del35) and a missence mutation in MCFD2 (p.D122V), identified in four patients, were novel mutations. A previously reported c.149 + 5G > A transition in MCFD2 was identified in the remaining five patients. Haplotype analysis of MCFD2 gene in patients with p.E71fs and c.149 + 5G > A defects suggested an independent origin of both these mutations. The identification of two common mutations (p.E71fs, c.149 + 5G > A) in MCFD2 gene in seven of nine patients, particularly the c.149 + 5G > A (55,6% of patients), suggests that this gene could be the first to be analysed during the genetic diagnosis of F5F8D in this population. This is the first report describing the molecular analysis of a consistent number of F5F8D patients of South Indian origin, a population with a high frequency of such recessive bleeding disorders.
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: G
authors.initials: G
authors.lastname: Jayandharan
authors.forename: M
authors.initials: M
authors.lastname: Spreafico
authors.forename: A
authors.initials: A
authors.lastname: Viswabandya
authors.forename: M
authors.initials: M
authors.lastname: Chandy
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.forename: F
authors.initials: F
authors.lastname: Peyvandi
mesh_terms: D003241:Consanguinity; D004252:DNA Mutational Analysis / Q000379:methods; D005166:Factor V Deficiency / Q000235:genetics* / Q000378:metabolism; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007194:India; D008297:Male; D037241:Mannose-Binding Lectins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C084004:LMAN1 protein, human; C475146:MCFD2 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C078147:F8 protein, human; D005169:Factor VIII