Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort.
Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort.
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DOI：
10.1186/alzrt137
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发表时间：
2012-08-20
期刊：
影响因子：
--
通讯作者：
Cruchaga C
中科院分区：
文献类型：
--
作者：
Jin SC;Pastor P;Cooper B;Cervantes S;Benitez BA;Razquin C;Goate A;Ibero-American Alzheimer Disease Genetics Group Researchers;Cruchaga C
一些家族性阿尔茨海默病（AD）病例是由APP、PSEN1和PSEN2的罕见和高渗透突变引起的。在临床诊断的AD病例中发现了与额颞叶痴呆（FTD）相关的两个基因GRN和MAPT的突变。由于新一代测序技术（NGS）的巨大发展，在许多个体中对人类基因组的目标基因组区域进行单次高通量测序现在既便宜又可行。最近的研究结果支持罕见变异-常见病假说，根据该假说，罕见变异的组合效应可以解释很大一部分的遗传性。我们利用NGS在一个伊比利亚美洲队列中鉴定APP、PSEN1、PSEN2、GRN和MAPT的罕见和致病变异。我们对来自西班牙和乌拉圭的167例临床和5例尸检证实的AD病例（15例家族性早发性，136例散发性早发性，16例家族性晚发性）的APP、PSEN1、PSEN2、MAPT和GRN的每个外显子和侧边序列进行了NGS测序。随访基因分型用于验证变异。在对其他对照进行基因分型后，我们进行了分离和功能分析，以确定验证变异的致病性。我们在一个散发性早发性AD病例的PSEN1外显子6中发现了一个新的G到T的转变（G . 38816g >T），导致先前描述的致病性p.L173F突变。在一例家族性早发性AD病例中发现致病性p.L392V外显子11突变。我们还在GRN的第8外显子中发现了一个新的CC插入（g.10974_10975insCC），该插入引入了一个过早停止密码子，导致无义介导的mRNA衰变。与先前报道的其他GRN致病性突变一样，这种GRN突变与较低的GRN血浆水平有关。我们发现MAPT的两个变体（p.A152T, p.S318L）仅在三个AD病例中存在，而在对照组中不存在，这表明这些变体可能是该疾病的危险因素。在2.33%的筛查病例中发现PSEN1、GRN和MAPT的致病性突变。本研究提示，在临床AD病例中，MAPT和GRN的致病突变或危险变异与APP、PSEN1和PSEN2的突变一样频繁，强调MAPT或GRN突变的多效性可以影响FTD和AD的表型性状。
Some familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in APP, PSEN1, and PSEN2. Mutations in GRN and MAPT, two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the rare variant-common disease hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort. We performed pooled-DNA sequencing of each exon and flanking sequences in APP, PSEN1, PSEN2, MAPT and GRN in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants. We identified a novel G to T transition (g.38816G>T) in exon 6 of PSEN1 in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974_10975insCC) in exon 8 of GRN, which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This GRN mutation was associated with lower GRN plasma levels, as previously reported for other GRN pathogenic mutations. We found two variants in MAPT (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease. We found pathogenic mutations in PSEN1, GRN and MAPT in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in MAPT and in GRN are as frequent in clinical AD cases as mutations in APP, PSEN1 and PSEN2, highlighting that pleiotropy of MAPT or GRN mutations can influence both FTD and AD phenotypic traits.
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影响因子：
4.2
作者：
Kara E;Ling H;Pittman AM;Shaw K;de Silva R;Simone R;Holton JL;Warren JD;Rohrer JD;Xiromerisiou G;Lees A;Hardy J;Houlden H;Revesz T
通讯作者：
Revesz T
影响因子：
3.7
作者：
Cruchaga C;Haller G;Chakraverty S;Mayo K;Vallania FL;Mitra RD;Faber K;Williamson J;Bird T;Diaz-Arrastia R;Foroud TM;Boeve BF;Graff-Radford NR;St Jean P;Lawson M;Ehm MG;Mayeux R;Goate AM;NIA-LOAD/NCRAD Family Study Consortium
通讯作者：
NIA-LOAD/NCRAD Family Study Consortium
影响因子：
5.3
作者：
HIMMLER, A
通讯作者：
HIMMLER, A
影响因子：
4.2
作者：
Benussi, Luisa;Binetti, Giuliano;Ghidoni, Roberta
通讯作者：
Ghidoni, Roberta
影响因子：
56.9
作者：
LEVYLAHAD, E;WASCO, W;TANZI, RE
通讯作者：
TANZI, RE