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Genetic Basis of Human Complement C8- Deficiency¹

Takeshi Kojima^*, Takahiko Horiuchi^2,*, Hiroaki Nishizaka^*, Yasuo Fukumori, Tetsuki Amano, Kohei Nagasawa^§, Yoshiyuki Niho^* and Kenshi Hayashi^¶

^* First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan; Department of Research, Osaka Red Cross Blood Center, Osaka, Japan; Third Department of Internal Medicine, Faculty of Medicine, Okayama University, Okayama, Japan; ^§ Department of Internal Medicine, Saga Medical School, Saga, Japan; and ^¶ Institute of Genetic Information, Kyushu University, Fukuoka, Japan

Deficiency of the - subunit of the eighth component of complement (C8-D) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular basis of C8-D in two unrelated Japanese subjects. Screening all 11 exons of the C8 gene and all 7 exons of the C8 gene and their boundaries by exon-specific PCR/single-strand conformation polymorphism demonstrated aberrant single-stranded DNA fragments in exon 2 of C8 gene in case 1 and in exons 2 and 9 of C8 gene in case 2. Nucleotide sequencing of the amplified DNA fragments in case 1 revealed a homozygous single-point mutation at the second exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the second intron (IVS2+1GT). Case 2 was a compound heterozygote for the splice junction mutation, IVS2+1GT, and a nonsense mutation at Arg³⁹⁴ (R394X). R394X was caused by a C to T transition at nucleotide 1407, the first nucleotide of the codon CGA for Arg³⁹⁴, leading to a stop codon TGA. No mutations were detected in the C8 gene by our method. Our results indicate that the pathogenesis of C8-D might be caused by heterogeneous molecular defects in the C8 gene.

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