Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Neurodegener Dis. 2010;7(1-3):170-4. doi: 10.1159/000289231. Epub 2010 Mar 3.
Hippocampal sclerosis (HpScl) is common in elderly subjects with dementia, either alone or accompanied by other pathologic processes. It is also found in >70% of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). TDP-43 inclusions are detected in >20% of Alzheimer disease (AD) and >70% of HpScl cases. The most common cause of FTLD-TDP is mutation in the progranulin gene (GRN). Recently, a common genetic variant in the 3' untranslated region (3'UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls.
The goal of this study was to determine if the 3'UTR variant in GRN was associated with TDP-43 immunoreactivity in AD with and without HpScl.
644 cases of pathologically confirmed AD, including 57 with HpScl, were screened for TDP-43 immunoreactivity and were genotyped at the GRN 3'UTR single-nucleotide polymorphism rs5848 using previously published methods.
There was a trend (p = 0.06) for TDP-43 immunoreactivity, but a very significant (p = 0.005) association of HpScl with the variant, with 72% of AD with HpScl carrying a T-allele, compared to 51% of AD without HpScl carrying a T-allele.
The results suggest that a genetic variant in GRN leading to decreased levels of progranulin may be a risk factor for HpScl in AD, while its role in TDP-43 immunoreactivity in AD remains less certain.
海马硬化（HpScl）在老年痴呆症患者中很常见，无论是单独存在还是伴有其他病理过程。它也存在于 >70%的伴有 TDP-43 免疫反应性包含物的额颞叶变性（FTLD-TDP）中。TDP-43 包含物在 >20%的阿尔茨海默病（AD）和 >70%的 HpScl 病例中被检测到。FTLD-TDP 的最常见原因是颗粒蛋白前体基因（GRN）的突变。最近，GRN 的 3'非翻译区（3'UTR）中的一个常见遗传变异（rs5848；c.*78C>T）位于 microRNA 结合位点，调节颗粒蛋白的表达，与对照组相比，T 等位基因在 FTLD-TDP 中增加。
本研究的目的是确定 GRN 的 3'UTR 变异是否与伴有和不伴有 HpScl 的 AD 中的 TDP-43 免疫反应性有关。
对 644 例经病理证实的 AD 病例进行筛选，包括 57 例伴有 HpScl 的病例，使用先前发表的方法，对 GRN 3'UTR 单核苷酸多态性 rs5848 进行 TDP-43 免疫反应性检测和基因分型。
TDP-43 免疫反应性有趋势（p=0.06），但 HpScl 与该变异的相关性非常显著（p=0.005），72%的伴有 HpScl 的 AD 携带 T 等位基因，而不伴有 HpScl 的 AD 携带 T 等位基因的比例为 51%。
结果表明，GRN 中的遗传变异导致颗粒蛋白水平降低可能是 AD 中 HpScl 的一个危险因素，而其在 AD 中 TDP-43 免疫反应性的作用仍不太确定。
