Mutations in the MCFD2 gene are predominant among patients with hereditary combined FV and FVIII deficiency (F5F8D) in India

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia 2007-07, Vol.13 (4), p.413-419
• Main Authors: JAYANDHARAN, G., SPREAFICO, M., VISWABANDYA, A., CHANDY, M., SRIVASTAVA, A., PEYVANDI, F.
• Format: Article
• Language: English
• Subjects: combined FV and FVIII deficiency; Consanguinity; DNA Mutational Analysis - methods; F5F8D; Factor V Deficiency - genetics; Factor V Deficiency - metabolism; Factor VIII - genetics; Factor VIII - metabolism; Female; Hemophilia A - genetics; Heterozygote; Homozygote; Humans; India; LMAN1; Male; Mannose-Binding Lectins - genetics; Mannose-Binding Lectins - metabolism; MCFD2; Membrane Proteins - genetics; Membrane Proteins - metabolism; mutation; Mutation - genetics; Pedigree; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/j.1365-2516.2007.01477.x

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.