In the following I want to give an impression of Katja Becker’s and my efforts to tackle the task of assessing the severity of some mutations that affect hearing in humans with the help of some bioinformatic tools. Using the known structure of a rat enzyme (catechol-O-methyltransferase) which controls the synthesis of some neurotransmitters and which is quite similar to the human enzyme, we were able to examine the influences of some amino acid substitutions on the function of this enzyme. Tab. 1 mainly summarizes the mutations we used and Fig. 1 focuses on the locations of the mutations within the enzyme described in Tab. 1. Based on those positions it is possible to determine the severity of amino acid mutations when the spatial structure and the functional properties of the used enzyme are known. The following documents displays some of our main results.

Tab. 1: The table shows the type of mutation and the match of this region with the rat LRTOMT.
The sequences are conserved except for No. 2 and 6. The severity and the location of the mutation define
the phenotype.

No. Mutation Human sequence Rat structure (position) Effect of the mutation Phenotype
1 P155A LPPGG LQPGA (82) Turn might not be formed Hearing impairment
2 Y111L CEYLS KEWAM (38) Effect on active site entrance Severe deafness
3 G143A YCGYS YCGYS (70) Affects the ligand binding pocket Severe deafness
4 V212A DLVLL DMVFL (138) No significant structural changes Hearing impairment
5 D224S LRDLQ LPDTL (150) Indirect effect on ligand binding site Severe deafness
6 H244L ADHVL ADNVI (170) No metal ion binding Severe deafness

Fig. 1 - for more information contact the authors.

Fig. 2: The crystal structure of rat catechol-O-methyltransferase (COMT) which is homologue to the human COMT. The ligands are coloured in yellow and the arrow points at the metal binding site. The gray molecule symbolizes magnesium. All six present mutations are represented with their name and location.


For references request the original file from the authors.