Digging deeper into TBR1 Genetics
As a small group of parents we are fortunate to have a scientist in our midst. Qing Chen is the mother of Landi, a lovely boy with a TBR1 genetic mutation. Qing is also a biologist, aiming to get her PhD degree in 2021.
Because of Qing, we have this extra page on our website that is interesting for the curious among us. Qing dives deeper into TBR1 information and applies this to our small group. She writes in such a way that she makes it easier to non-scientists among us to understand the difficult field of genetics. If you have questions after reading this, please contact us.
Qing Chen, december 2020 (will be updated soon):
The individuals in our Facebook group who have shared their or their child’s specific mutation are viewed in the above figure. Of these 15 individuals, all but one are de novo mutations. De novo means new, not inherited from family. All the human mutations are heterozygous so that the normal TBR1 from an intact chromosome still functions in the body.
In January 2020, Dr. Christel Thauvin-Robinet’s team published a paper to describe 38 cases with de novo TBR1 mutations(1). Some of the families know each other from this study. Interestingly, we found four identical mutations, p.T532R fs*144, in our group. The four families in our group have found more consistency during the everyday life. There are eight additional p.T532R fs*144 in the Dr. Thauvin-Robinet’s study1. So p.T532R fs*144 could be the most common TBR1 mutation in the world.
p.P25A is the only inherited mutant in our group. The young man learned more information about inherited mutant from our chatting in the group. Our team provided the evidences his family is not the only one with inherited TBR1 mutant. In 2014, Dr. Simon E. Fisher published four inherited mutants(2).
I made the figure based on a figure in Dr. Simon E. Fisher’s paper(2). The TBR1 protein contains 682 amino acids. We use a white box with a blue one inside to represent the protein. There are five missense mutations (on the top of the box) and six frameshift mutations (on the bottom of the box) with 15 individuals. In one missense mutation, only one amino acid is replaced /mutated in the TBR1 protein. The number indicates the location of the mutation site. The capital letters represent the amino acids. The lowercase letter p stands for protein.
The same abbreviations are applied in the frameshift mutations on the bottom. Fs is the abbreviation of frameshift. A star * means alternate stop code. The number after the star indicates the location of the alternate stop code. A stop code is a command for a protein translation. An alternate stop code produces a truncated protein. If the truncated protein is short, such as p.L106 fs*, the mutant protein probably processes non-sense mediated RNA decay. In other words, only normal/ wildtype TBR1 protein would work in the bodies because the truncated protein would be cleaned by the body itself. However, the amount of functional TBR1 protein would be the half of the neurotypical individuals.
If the mutant protein could not be cleaned by the body itself, the condition would be worse. There is a dimerization domain in the TBR1 protein. Dimer means two so that dimerization is a process that two proteins couple together for a function. In a normal kid, a pair of TBR1 proteins should work together with the normal dimerization domain. In a kid with TBR1 mutant, if the dimerization domain still works, the bad TBR1 protein will couple with a good TBR1 protein so that the good TBR1 protein could not work functionally.
TBR1 is a transcription factor for the brain development. A transcription factor needs to bind DNA sequence on other genes for activation or repression. According to Dr. Fisher’s paper, T-box is a highly conserved DNA binding domain(2). That means all the vertebrate animals including fish and mouse needs the same sequence of T-box in the TBR1 to bind DNA for the transcription activation/ repression. A missense mutation in the T-box sequence may impair the ability of DNA binding. If the dimerization domain is intact, the missense mutation may undermine the function of the normal TBR1. FOXP2 interacting and CASK interacting regions are important in the TBR1. Dr. Fisher’s paper elucidated the molecular mechanism(2).
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