Molecular Genetic Analysis of Factor XI Deficiency: Identification of Five Novel Gene
Alterations and the Origin of Type II Mutation in Portuguese Families
Célia Ventura
1
From the Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge,
Lisboa, UK
,
Ana I. M. Santos
1
From the Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge,
Lisboa, UK
,
Alice Tavares
2
Serviço de ImunoHemoterapia, Hosp. St. Maria, Lisboa, UK
,
Teresa Gago
3
Lab. de Patologia Clinica, Hosp. de Santa Cruz, Carnaxide, Portugal, UK
,
João Lavinha
1
From the Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge,
Lisboa, UK
,
John H. McVey
4
Haemostasis Research Group, MRC Clinical Sciences Centre, ICSM, Hammersmith Hospital,
London, UK
,
Dezsö David
1
From the Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge,
Lisboa, UK
› Author Affiliations The authors thank Drs G. de Deus, M. J. Diniz and M. Campos for referring three of
the analysed families to us. This research was partially supported by research grant
SAU/1588/92 from Fundação para a Ciência e Tecnologia (FCT). Ana I. M. Santos was supported by a research scholarship from FCT.
Coagulation factor XI (FXI) deficiency is an inherited autosomal recessive mild bleeding
disorder. In this study, we report the molecular genetic analysis of FXI deficiency
in six unrelated families of Portuguese origin. The Jewish type II mutation was found
in two families, of seemingly Portuguese origin. Haplotype analysis in these families
demonstrated that this mutation is of Jewish origin. In the remaining families, five
novel FXI mutations have been identified. Two of these mutations (FXI IVS K -10T→A
and FXI 1026G→T, cd 324) affect the FXI pre-mRNA splicing. A further two (FXI 307
ins AAGCAAT, cd 85 and FXI 1072 del A, cd 340) introduce frameshifts leading to premature
termination codons. The FXI splicing mutation, 1026G→T cd 324, was found in compound
heterozygosity with missense mutation FXI K518N. Analysis of the FXI mRNA from the
latter genotype demonstrated new donor splice site usage. All reported mutations most
likely result in functional null-alleles. In addition, three novel polymorphisms have
been identified: at nt -138 in intron A, at codon D125 in exon 5 and at codon T249
in exon 8.
Key words
FXI deficiency -
phenotype -
FXI mutations -
FXI pre-mRNA splicing -
origin of the type II mutation
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