Heterogeneity within a large kindred with frontotemporal dementia - A novel progranulin mutation
Heterogeneity within a large kindred with frontotemporal dementia - A novel progranulin mutation
复制标题
DOI：
10.1212/01.wnl.0000265220.64396.b4
复制
发表时间：
2007-07-10
期刊：
影响因子：
9.9
通讯作者：
Rogaeva, E.
中科院分区：
文献类型：
--
作者：
Bruni, A. C.;Momeni, P.;Rogaeva, E.
背景：最近通过截断原颗粒基因(GRN)突变来解释几个17q21连锁家系的额颞部痴呆(FTD)。目的：确定一组高加索FTD患者中GRN基因突变的频率。方法：对78例FTD患者(包括23例家族性受试者)进行GRN测序。使用不同的Calabrian数据集(109名正常对照受试者和96名FTD患者)来确定GRN突变的频率。结果：在一个广泛血缘的卡拉布里亚家系的先证者中发现了一种新的截短GRN突变(c.1145insA)。对70个家系成员进行分离分析，发现19个杂合子突变携带者，其中9例为FTD患者。高度血缘关系的家系中没有纯合子携带者可能表明两个GRN等位基因的缺失可能导致胚胎死亡。突变携带者的发病年龄极不稳定(相隔50多年)，不能用APOE基因或H1/H2 MAPT单倍型来解释。有趣的是，在属于FTD常染色体显性遗传模式的分支的4名FTD患者中排除了该突变，这表明另一种新的FTD基因解释了表型上的疾病。临床上很难区分显性表型和GRN突变携带者，除非突变携带者的语言受到更严重的损害。结论：目前的结果提示额颞部痴呆的遗传异质性进一步加深，因为我们只检测到一个GRN连锁家系(约1%)。发现大家族的价值包括对GRN突变携带者进行纵向研究的可能性。
Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. Methods: 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. Results: 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. Conclusion: 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.