Nishizaka H, Horiuchi T, Zhu Z B, Fukumori Y, Nagasawa K, Hayashi K, Krumdieck R, Cobbs C G, Higuchi M, Yasunaga S, Niho Y, Volanakis J E
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
J Immunol. 1996 Mar 15;156(6):2309-15.
Deficiency of the sixth component of complement (C6D) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular bases of C6D in two unrelated subjects, one African American (case 1) and the other Japanese (case 2). Screening all 17 exons of the C6 gene and their boundaries by exon-specific PCR/single strand conformation polymorphism demonstrated aberrant single stranded DNA fragments in exon 12 of case 1 and exon 2 of case 2. Nucleotide sequencing of the amplified DNA fragments revealed a homozygous single-base deletion (G1936) in exon 12 case 1 and a heterozygous single base deletion (C291/C292/C293/C294) in exon 2 of case 2. Both mutations resulted in frame shifts and premature termination of the C6 polypeptide. Sequence-specific oligonucleotide probe hybridization and direct sequencing of exon 12 amplified from genomic DNA further supported the homozygosity of the mutation in case 1. Case 2 is apparently compound heterozygote, but the putative mutation in the other allele of the C6 gene remains unknown. Both case 1 and case 2 were homozygous for the C6A allotype. These data indicate that at least three distinct mutational events can cause C6D, single nucleotide deletions in exons 2 and 12, and a mutation yet unidentified. Thus, similar to other complement protein deficiencies, the pathogenesis of C6D appears to be heterogeneous.
补体第六成分缺乏症（C6D）常与奈瑟菌反复感染相关，尤其是由脑膜炎奈瑟菌引起的脑膜炎。我们在此报告两名无关个体中C6D的分子基础，一名非裔美国人（病例1），另一名日本人（病例2）。通过外显子特异性PCR/单链构象多态性筛查C6基因的所有17个外显子及其边界，结果显示病例1的外显子12和病例2的外显子2中存在异常单链DNA片段。对扩增的DNA片段进行核苷酸测序，结果显示病例1的外显子12中存在纯合单碱基缺失（G1936），病例2的外显子2中存在杂合单碱基缺失（C291/C292/C293/C294）。这两种突变均导致C6多肽的移码和提前终止。序列特异性寡核苷酸探针杂交以及从基因组DNA扩增的外显子12的直接测序进一步支持了病例1中突变的纯合性。病例2显然是复合杂合子，但C6基因另一个等位基因中的推定突变仍然未知。病例1和病例2的C6A同种异型均为纯合子。这些数据表明，至少三种不同的突变事件可导致C6D，即外显子2和12中的单核苷酸缺失，以及一种尚未确定的突变。因此，与其他补体蛋白缺乏症类似，C6D的发病机制似乎具有异质性。
