TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a causative gene of both amyotrophic lateral sclerosis (ALS) and frontotemporal lober degeneration (FTLD), based on the findings that ubiquitin-positive cytoplasmic inclusion bodies in ALS and FTLD pathology primarily contain the TDP-43 protein, and that both familial and sporadic patients have point mutations in the genes. However, the relationship between pathogenesis and the accumulation of the inclusions, and the multimodal/ exclusive linkage of ALS with FTLD are still unrevealed. Here, we investigated the causal role between the gene mutation and the ALS/ FTLD phenotypes using knock-in mice. First, we picked up two mutation points in the TDP-43 gene from the mutation found in both familial and sporadic ALS patients by the observation of cultured cell, by which we found the multimodal structures of the inclusions caused by each mutation point. (The structural difference depended on aging.) Next, we generated two types of mutated TDP-43 knock in (mTDP-43 KI) mice in order to investigate physiological effects of mutation points to biology and disease. Considerable differences in phenotypes were observed among mTDP-43 KI mice and wild type mouse. Poor weight gain which is related to ALS was detected in mTDP-43 mice, and decrease in anxiety levels which related to FTLD was observed in one of mTDP-43 KI mouse but not another mTDP-43 KI mouse. This indicated that mutation points were supposed to be predominat factor which sink into multimodal or exclusive pathologies. Our results which based on reference of TDP-43 mutations are useful information for therapeutic strategy of ALS and FTLD.