Most GLUT1 disease mutations are fairly subtle single amino acid substitutions l

Question

Most GLUT1 disease mutations are fairly subtle single amino acid substitutions like those described below. Why might it be that there are no known GLUT1 mutations that cause more global structural perturbations in the transporter?

Below is the crystal structure of the inward facing conformation of GLUT1 showing the location of mutations found in certain GLUT1 deficiency syndrome patients: N34I, N34S, N34Y, S294P, T295M and T310I. N34 is in TM1, S294 and T295 are in TM7 and T310 is in TM8. The residues cluster to a region of interaction between TM helices TM7, TM8 and TM1 that are proposed to function as an extracellular gate stabilizing the inward facing conformation

Explanation / Answer

GLUT 1 is the major glucose transporter and the 492 amino acid sequence protein is highly conserved. In case of any mutations seen, it would lead to formation of a premature or truncated GLUT 1 and this mRNA is rapidly degraded. In other words mutant RNAs are not expressed and therefore very obvious structural perturbations are not seen.

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