We read with great interest the article by Nambot et al. [1], in which 25 unreported individuals with mutations in the TBR1 gene were analyzed in great detail at molecular and anatomical levels and that also provides detailed clinical features of the patients. Since the patients carry de novo mutations, only one of their TBR1 alleles is mutated. Among the 25 patients, seven individuals were carefully analyzed by magnetic resonance imaging (MRI). Interestingly, a specific white matter structure of the brain, the anterior commissure (AC), is either thin or absent from all seven of those individuals. Other morphological abnormalities—including dysplastic hippocampi and/or cerebral cortex, severe gyral anomalies, and microcephaly—are present in only some of the patients. Thus, reduction of the AC is the most common anatomical feature shared by patients carrying different mutations in the TBR1 gene, although the Nambot et al. study did not quantify AC size.

These results are significant to study of TBR1. In two previous studies using Tbr1+/− mice, which mimic the condition of monoallelic mutations that result in early translational termination, small or absent ACs were identified upon hematoxylin and eosin staining, luxol fast blue/cresyl violet staining and MRI analysis [2, 3]. Note that the AC has both anterior and posterior parts. In the first of those two studies, histological methods revealed that the posterior part of the AC is the most sensitive structure to Tbr1 haploinsufficiency [2]. Later, in the second study, more comprehensive analyses using MRI supported the findings of the first study and further demonstrated that the anterior part of the AC is also affected by Tbr1 haploinsufficiency [3]. Apart from these two papers, another study used adeno-associated virus (AAV) for expression of YFP-tagged membrane protein to trace axonal projection via the AC. The results suggest that the two amygdalae in the two brain hemispheres do not project to each other via the AC in Tbr1+/− mice, which is in contrast to wild-type littermates [4]. Thus, the small or absent AC is the most critical phenotype of Tbr1+/− mice. The patient study contributed by Nambot and colleagues corroborates these mouse studies, further indicating that the AC defects caused by TBR1 deficiency are evolutionarily conserved between human and mice.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD