A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy
A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy
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DOI：
10.3233/jad-151170
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Logroscino, Giancarlo
中科院分区：
文献类型：
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作者：
Sassi, Celeste;Capozzo, Rosa;Logroscino, Giancarlo
颗粒蛋白杂合性功能突变缺失是泛素和TDP-43内含物（FTLD-TDP）引起额颞叶变性的重要原因。我们报告了一种新的GRN剪接位点突变（c. 709-2 a > T），在意大利南部的一个大家族中与额颞叶痴呆谱系分离。预计GRN c. 709-2 A> T会导致外显子8的跳跃，导致无义介导的mRNA衰变。此外，与对照组（142.7 ng/ml）或家族成员非携带者（82.0 ng/ml）相比，GRN c. 709-2 A> T携带者的PGRN血浆水平（24 ng/ml）显著降低（p值= 0.005,KruskalWallis），提示蛋白前单倍功能不全。在同一地理区域的6个FTD家族和43例散发性FTD病例的随访队列中，我们未报告任何潜在的致病性GRN突变。我们的研究表明，GRN （c. 709-2 A> T）是意大利队列中一种新颖且可能非常罕见的FTD病因。最后，与之前的研究一致，我们发现GRN单倍体功能不全导致临床表现不一致，血浆前颗粒蛋白水平可能是鉴定GRN功能缺失突变的可靠工具。然而，考虑到a)遗传和环境因素、性别和年龄可能调节PGRN血浆水平，b)血浆前颗粒蛋白水平可能不能反映PGRN在中枢神经系统中的水平，我们建议血浆中前颗粒蛋白的测量应始终与GRN突变的遗传筛查相结合。
Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c. 709-2 A> T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c. 709-2 A> T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c. 709-2 A> T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, KruskalWallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c. 709-2 A> T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.