RARE TRANSTHYRETIN MUTATION (ASP18GLU) ASSOCIATED WITH CARDIOMYOPATHY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在一名活检证实为淀粉样蛋白病的中年男性患者中，发现了一种罕见的甲状腺转甲状腺素（TTR）基因突变（Asp18Glu）。最初考虑的是更常见的轻链淀粉样变性（AL），但血液学检测阴性提示筛查病理性TTR突变。采用分子遗传学和生化技术相结合的方法建立了家族性转甲状腺素型淀粉样变性（ATTR）的鉴别诊断。TTR基因外显子2、3、4的单链构象多态性（SSCP）筛选显示存在非典型DNA。SSCP检测采用一种新的无放射性，银染色minigel技术。通过直接DNA序列分析鉴定该遗传异常为密码子18第3个碱基的T向a翻转。该结果经限制性片段长度多态性（RFLP）检测证实。先证者血清中存在变异蛋白TTR Asp18Glu，通过BUSM MS资源的质谱分析证实。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The identification of a rare transthyretin (TTR) gene mutation (Asp18Glu) in a middle-aged male with biopsy proven amyloid disease featuring cardiomyopathy was achieved. The more commonly occurring light chain amyloidosis (AL) was initially considered, but negative hematologic testing prompted screening for a pathologic TTR mutation. A differential diagnosis of familial transthyretin type amyloidosis (ATTR) was established using a combination of molecular genetic and biochemical techniques. Single-strand conformation polymorphism (SSCP) screening of exons 2, 3 and 4 of the TTR gene indicated the presence of atypical DNA. SSCP testing was performed using a new non-radioactive, silver stained minigel technique. The genetic abnormality was identified by direct DNA sequence analysis as a T to A transversion at the third base position in codon 18. This result was confirmed by restriction fragment length polymorphism (RFLP) testing. The presence of the variant protein, TTR Asp18Glu, in serum from the proband was confirmed by mass spectrometric analysis at the BUSM MS Resource.