Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series
Progranulin genetic variations in frontotemporal lobar degeneration: evidence for low mutation frequency in an Italian clinical series
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DOI：
10.1007/s10048-008-0127-3
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发表时间：
2008-07-01
期刊：
影响因子：
2.2
通讯作者：
Padovani, Alessandro
中科院分区：
文献类型：
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作者：
Borroni, Barbara;Archetti, Silvana;Padovani, Alessandro
额颞叶变性（FTLD）的家族发病率很高，据报道，高达50%的患者有类似痴呆症的家族史。据报道，在美国和世界范围内，颗粒蛋白前体（PGRN）基因内的突变是FTLD的主要原因，占FTLD的5-10%，占常见FTLD病例的20-25%。本研究的目的是确定PGRN遗传变异在意大利连续FTLD患者大样本中的作用。对243例FTLD患者进行了调查。每例受试者进行了临床和神经心理学评估，功能和结构脑成像，并通过至少1年的随访确认诊断。在所有FTLD患者和来自同一地理区域的121名健康年龄匹配对照中进行PGRN测序。仅发现一个PGRN致病突变，包括外显子8编码序列中的四个碱基对缺失（delCACT）。该突变在4例患者中被识别，在我们的临床系列中突变的总频率为1.64%。仅考虑具有痴呆症家族史的患者，这种突变的频率为6%。此外，在内含子区域发现了4个错义突变（g.100474G > A，g.100674G > A，g.101266G > A，g.102070G > A），这些基因变异在患者和对照组中的频率没有差异，也不影响FTLD的临床表型。总之，与文献数据相比，本研究支持意大利FTLD患者中PGRN突变频率较低，并进一步证实了FTLD的遗传异质性。
Frontotemporal lobar degeneration (FTLD) recognises high familial incidence, with up to 50% of patients reported to have a family history of similar dementia. It has been reported that mutations within progranulin (PGRN) gene are a major cause of FTLD in the USA and worldwide, counting for 5-10% of FTLD and for 20-25% of familiar FTLD cases. The aim of the present study was to define the role of PGRN genetic variations in a large sample of consecutive patients with FTLD in Italy. Two-hundred forty-three FTLD patients were investigated. Each subject performed a clinical and neuropsychological evaluation, a functional and structural brain imaging, and the diagnosis was confirmed by at least 1 year follow-up. PGRN sequencing was performed in all FTLD patients and in 121 healthy age-matched controls drawn from the same geographic area. Only one PGRN pathogenetic mutation was found, consisting of a four-base pair deletion in the coding sequence of exon 8 (delCACT). This mutation was recognised in four patients, being the overall frequency of mutations in our clinical series of 1.64%. Considering only patients with a well-known family history for dementia, the frequency of this mutation was 6%. Moreover, four missense mutations within intron regions (g.100474G > A, g.100674G > A, g.101266G > A, g.102070G > A) were found. The frequency of these genetic variations did not differ in patients compared to controls, and they did not influence on clinical FTLD phenotype. In conclusion, this study supports a lower frequency of PGRN mutations amongst FTLD patients in Italy compared to literature data and further underlies the genetic heterogeneity of FTLD.