C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic.
C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic.
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发表时间：
2012
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通讯作者：
Aleksandra M. Wojtas;Kristin A Heggeli;N. Finch;M. Baker;M. Dejesus‐Hernandez;S. Younkin;D. Dickson;N. Graff-Radford;R. Rademakers
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作者：
Aleksandra M. Wojtas;Kristin A Heggeli;N. Finch;M. Baker;M. Dejesus‐Hernandez;S. Younkin;D. Dickson;N. Graff-Radford;R. Rademakers
阿尔茨海默病(AD)和额颞性痴呆(FTD)是两种常见的临床症状重叠的原发性神经退行性痴呆。淀粉样前体蛋白(APP)和早老素1和2(PSEN1，PSEN2)基因的致病突变与家族性早发性AD有关；然而，最近在临床诊断的AD患者中也报道了编码微管相关蛋白tau(MAPT)、原颗粒(GRN)和C9ORF72的常见FTD基因的突变。为了了解突变在一系列特征良好的患者中的作用，我们在1997年至2011年期间在佛罗里达州梅奥诊所证实的227名临床诊断为可能的AD先证者的新队列中系统地进行了这些Eoad和FTD基因的遗传分析。所有患者在70岁之前都出现了痴呆的首发症状。我们在11名患者中发现了9种不同的Eoad基因致病突变，占患者总数的4.8%。有两个新突变：PSEN1 p.Pro218Leu和PSEN2p.Phe183Ser。重要的是，在所有FTD基因中也发现了突变：一名患者携带MAPT p.R406W突变，一名患者携带GRN中P.Arg198Glyfs19X功能缺失突变，两名患者被发现在C9ORF72的非编码区携带扩大的GGGGCC重复序列。FTD基因加在一起解释了1.8%的可能AD人群的疾病。在这一新的临床诊断AD患者队列中所有主要FTD基因突变的鉴定突显了由于症状重叠而导致的AD和FTD鉴别诊断的挑战，并对临床诊断AD患者的分子诊断测试和遗传咨询具有重要意义。我们的发现表明，在临床诊断的AD患者中，基因分析不仅应该包括成熟的Eoad基因APP、PSEN1和PSEN2，还应该包括通常与FTD相关的基因。最后，在我们的研究中观察到的突变携带者的总体低频率(6.6%)表明与AD相关的其他未知遗传因素的参与。
Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD; however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT), progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia before 70 years. We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining 4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly, mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of other as yet unknown genetic factors associated with AD.