Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic κ1 light chain
Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic κ1 light chain
复制标题
DOI：
10.1016/s0925-4439(99)00019-8
复制
发表时间：
1999-05-31
影响因子：
6.2
通讯作者：
Comenzo, RL
中科院分区：
文献类型：
--
作者：
Wally, J;Kica, G;Comenzo, RL
目前关于免疫球蛋白 (Ig) 轻链结构与 AL 淀粉样变性 (AL) 之间关联的概念强调 Ig 可变区氨基酸取代，因为已测序的大多数轻链淀粉样原纤维含有可变区的氨基末端，仅含有少量恒定区。在本报告中，我们描述了一位患有快速进展性 AL 的患者，其淀粉样蛋白沉积物主要含有单克隆 kappa 轻链恒定区片段。我们对这种 AL 蛋白进行了测序和分析，确定它是 O18-O8 kappa(1) 变体，并且恒定区在第 177 位具有不寻常的 Ser --> Asn 替换。使用死前骨髓细胞，我们对这种 AL 蛋白 (HCAK1) 的 cDNA 进行了克隆和测序，并使用来自死后体细胞组织的 DNA，对患者的 kappa 种系 O18-O8 供体进行了克隆和测序。 kappa 恒定区 (C kappa) 基因片段。编码 HCAK1 的 cDNA 包含一个源自 O18-O8 的可变区，与种系有 96.1% 同源性，以及一个具有核苷酸取代（AGC 至 AAC）的 C kappa，导致 177(Ser-Asn) 取代。从体细胞组织 DNA 中克隆了两个 C kappa 基因，一个与已知的 C kappa 序列相同，另一个包含这种替换，这可能是一种新的 C kappa 同种异型。我们的研究结果表明，有必要进一步研究遗传多态性和轻链恒定区对淀粉样蛋白生成的贡献。 (C) 1999 Elsevier Science B.V. 保留所有权利。
Current concepts regarding the association between immunoglobulin (Ig) light chain structure and AL amyloidosis (AL) emphasize Ig variable region amino acid substitutions because the majority of light chain amyloid fibrils that have been sequenced contain amino termini of the variable region with only small amounts of the constant region. In this report, we describe a patient with rapidly progressive AL whose amyloid deposits contained primarily monoclonal kappa light chain constant region fragments. We sequenced and analyzed this AL protein, determining that it was an O18-O8 kappa(1) variant and that the constant region possessed an unusual Ser --> Asn substitution at position 177. Using pre-mortem bone marrow cells, we cloned and sequenced the cDNA for this AL protein (HCAK1) and, using DNA from post-mortem somatic tissue, we cloned and sequenced the patient's kappa germline O18-O8 donor and kappa constant region (C kappa) gene segments. The cDNA that coded for HCAK1 contained a variable region that was derived from O18-O8, showing 96.1% homology to germline, and a C kappa that had a nucleotide substitution (AGC to AAC), resulting in the 177(Ser-Asn) replacement. Two C kappa genes were cloned from somatic tissue DNA, one identical to a known C kappa sequence and another containing this substitution which likely is a new C kappa allotype. Our findings indicate that further investigation is warranted into the contributions genetic polymorphisms and light chain constant regions may make to amyloidogenesis. (C) 1999 Elsevier Science B.V. All rights reserved.