Despite the strong genetic component of frontotemporal dementia (FTD), a substantial proportion of patients remain genetically unresolved. We performed an in-depth study of a family with an autosomal dominant form of FTD to investigate the underlying genetic cause.

Following clinical and pathologic characterization of the family, genetic studies included haplotype sharing analysis and exome sequencing. Subsequently, we performed immunohistochemistry, immunoblotting, and a microtubule repolymerization assay to investigate the potential impact of the candidate variant in tubulin alpha 4a (TUBA4A).

The clinical presentation in this family is heterogeneous, including behavioral changes, parkinsonian features, and uncharacterized dementia. Neuropathologic examination of 2 patients revealed TAR DNA binding protein 43 (TDP-43) pathology with abundant dystrophic neurites and neuronal intranuclear inclusions, consistent with frontotemporal lobar degeneration–TDP type A. We identified a likely pathogenic variant in TUBA4A segregating with disease. TUBA4A encodes for α-tubulin, which is a major component of the microtubule network. Variants in TUBA4A have been suggested as a rare genetic cause of amyotrophic lateral sclerosis (ALS) and have sporadically been reported in patients with FTD without supporting genetic segregation. A decreased trend of TUBA4A protein abundance was observed in patients compared with controls, and a microtubule repolymerization assay demonstrated disrupted α-tubulin function. As opposed to variants found in ALS, TUBA4A variants associated with FTD appear more localized to the N-terminus, indicating different pathogenic mechanisms.

Our findings support the role of TUBA4A variants as rare genetic cause of familial FTD.

尽管额颞叶痴呆（FTD）具有很强的遗传因素，但仍有相当一部分患者的遗传问题仍未得到解决。我们对一个患有常染色体显性遗传 FTD 的家庭进行了深入研究，以调查潜在的遗传原因。

根据该家族的临床和病理特征，遗传学研究包括单倍型共享分析和外显子组测序。随后，我们进行了免疫组织化学、免疫印迹和微管再聚合测定，以研究微管蛋白 α 4a ( TUBA4A ) 中候选变体的潜在影响。

该家族的临床表现多种多样，包括行为改变、帕金森病特征和不明特征的痴呆。 2 名患者的神经病理学检查显示 TAR DNA 结合蛋白 43 (TDP-43) 病理学具有丰富的营养不良性神经突和神经元核内包涵体，与额颞叶变性 - TDP A 型一致。我们在TUBA4A中发现了与疾病分离的可能致病变异。 TUBA4A编码 α-微管蛋白，它是微管网络的主要组成部分。 TUBA4A的变异被认为是肌萎缩侧索硬化症 (ALS) 的罕见遗传原因，并且在 FTD 患者中零星报道，但不支持基因分离。与对照组相比，患者中观察到TUBA4A蛋白丰度呈下降趋势，微管再聚合测定表明 α-微管蛋白功能受到破坏。与 ALS 中发现的变异相反，与 FTD 相关的TUBA4A变异似乎更定位于 N 末端，表明不同的致病机制。

我们的研究结果支持TUBA4A变异作为家族性 FTD 的罕见遗传原因的作用。