Histidine-rich glycoprotein (HRG) Tokushima 2: Novel HRG deficiency, molecular and cellular characterization

The proband, a 76-year-old woman, suffered from dural arteriovenous fistula . Her plasma histidine-rich glycoprotein (HRG) level was 50% of the normal level. A low level of plasma HRG was also found in her third daughter. A si ngle nucleotide substitution of T to C was found at nucleotide position 11, 438 in exon 6 of the HRG gene from the proband, converting Cys223 to Arg in the second cystatin-like domain. The same mutation was also identified in her third daughter, but not in the other four family members having normal HRG levels or in 50 unrelated healthy Japanese individuals. Expression stud ies in BHK cells showed that substantial intracellular degradation of the m utant occurred and only about 40% of the recombinant HRG mutant was secrete d. These results indicate that congenital HRG deficiency caused by a substi tution of Cys223 to Arg is hereditary in this family.