A novel mutation (Tyr503Cys) in a severe factor XI deficiency

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Inherited factor XI (FXI) deficiency is a bleeding disorder.
• Consanguineous marriages can increase the incidence of genetic disorders.
• Type II FXI deficiency is characterized by reduced FXI activity with normal FXI antigen levels.

Purpose of the Study:

• To investigate a novel gene mutation (Tyr503Cys) in a Chinese family with inherited factor XI deficiency.
• To determine the molecular basis of FXI deficiency in the studied family.

Main Methods:

• Factor XI (FXI) activity and antigen levels were measured using clotting assays and ELISA.
• The F11 gene was amplified via PCR and analyzed by direct sequencing.
• Bioinformatics tools (ClustalX-2.1-win and others) were used to assess mutation conservation and functional impact.

Main Results:

• The proband exhibited 13% FXI activity, while three other family members showed approximately 35% activity, all with normal FXI antigen levels.
• DNA sequencing identified a homozygous c.1562A>G point mutation in the F11 gene, leading to a Tyr503Cys substitution.
• Bioinformatics analysis confirmed Tyr503 is highly conserved and the mutation likely impairs protein function.

Conclusions:

• The Tyr503Cys mutation in the F11 gene is responsible for the observed cross-reacting material positive, type II factor XI deficiency.
• This represents the first report of the Tyr503Cys mutation causing FXI deficiency worldwide.