Bruni A C, Momeni P, Bernardi L, Tomaino C, Frangipane F, Elder J, Kawarai T, Sato C, Pradella S, Wakutani Y, Anfossi M, Gallo M, Geracitano S, Costanzo A, Smirne N, Curcio S A M, Mirabelli M, Puccio G, Colao R, Maletta R G, Kertesz A, St George-Hyslop P, Hardy J, Rogaeva E
Regional Neurogenetic Centre, Lamezia Terme, CZ, Italy.
Neurology. 2007 Jul 10;69(2):140-7. doi: 10.1212/01.wnl.0000265220.64396.b4.
Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN).
To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes.
GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation.
A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised.
The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.
最近，在几个与17q21连锁的家族性额颞叶痴呆（FTD）病例中发现，其病因是颗粒蛋白前体基因（GRN）发生了截短突变。
确定在一组已知FTD相关基因无突变的白种人FTD患者中GRN突变的频率。
对78例独立的FTD患者（包括23例家族性患者）进行GRN基因测序。使用另一个来自卡拉布里亚地区的数据集（109名正常对照者和96例FTD患者）来确定GRN突变的频率。
在一个来自卡拉布里亚地区的近亲大家族的先证者中检测到一种新的GRN截短突变（c.1145insA）。对70名家族成员进行的分离分析显示，有19名杂合突变携带者，其中9例为FTD患者。在一个高度近亲的家族中未发现纯合突变携带者，这可能表明GRN两个等位基因的缺失可能导致胚胎致死。突变携带者的发病年龄差异极大（相差超过50年），这无法用APOE基因型或H1/H2 MAPT单倍型来解释。有趣的是，在4例属于FTD常染色体显性遗传分支的FTD患者中排除了该突变，这表明在这些表型相似病例中，另一个新的FTD基因导致了疾病的发生。除了突变携带者的语言功能受损更严重外，临床上很难将表型相似病例与GRN突变携带者区分开来。
目前的研究结果表明额颞叶痴呆存在进一步的遗传异质性，因为我们仅检测到一个与GRN相关的家族（约1%）。发现大家族的价值在于有可能对GRN突变携带者进行纵向研究。
