Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration
Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration
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DOI：
10.1212/01.wnl.0000325058.10218.fc
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发表时间：
2008-10-14
期刊：
影响因子：
9.9
通讯作者：
Binetti, G.
中科院分区：
文献类型：
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作者：
Ghidoni, R.;Benussi, L.;Binetti, G.
背景：颗粒体蛋白前体基因（PGRN）突变被确定为额颞叶变性（FTLD）的致病机制。大多数突变预计会产生无效等位基因，导致颗粒体蛋白前体转录物丢失 50%。 方法：患者在意大利布雷西亚 IRCCS S. Giovanni di Dio-Fatebenefratelli 记忆诊所接受临床和神经学检查。我们招募了携带 FTLD 相关颗粒体蛋白前体 Leu271LeufsX10 突变的家庭中受影响的 (n = 6) 和未受影响的高危成员 (n = 73)；此外，我们还纳入了受散发性/家族性 FTLD 影响的受试者 (n = 65)、对照者 (n = 75) 以及携带 tau P301L 突变的家庭。通过外显子和侧翼内含子区域的直接测序来研究 PGRN 和 MAPT 基因突变的存在。使用 ELISA 测量颗粒体蛋白前体血浆和脑脊液水平。 结果：我们证明，携带颗粒体蛋白前体基因突变（PGRN Leu271LeufsX10 和 Q341X）的受影响和未受影响受试者的血浆和脑脊液中颗粒体蛋白前体蛋白均大幅降低（高达 3.93 倍）。我们建立了 74.4 ng/mL 的血浆颗粒体蛋白前体蛋白截止水平，可以以 100% 的特异性和敏感性识别未受影响受试者中的突变携带者。在 FTLD 中，值
Background: Mutations in the progranulin gene (PGRN) were identified as the causal mechanism underlying frontotemporal lobar degeneration (FTLD). Most of these mutations are predicted to create null alleles leading to a 50% loss of progranulin transcript.Methods: Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. We enrolled affected (n = 6) and unaffected at risk members (n = 73) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation; additionally, we included subjects affected by sporadic/familial FTLD (n = 65), controls (n = 75), and a family carrying the tau P301L mutation. The presence of mutations in PGRN and MAPT genes was investigated by direct sequencing of exonic and flanking intronic regions. Progranulin plasma and CSF levels were measured using ELISA.Results: We demonstrated that progranulin protein is strongly reduced (up to 3.93-fold) both in plasma and CSF of affected and unaffected subjects carrying mutations in progranulin gene (PGRN Leu271LeufsX10 and Q341X). We established a plasma progranulin protein cutoff level of 74.4 ng/mL that identifies, with specificity and sensitivity of 100%, mutation carriers among unaffected subjects. In FTLD, values