Pathogenic variants & ALD Protein Stability

Johannes Berger, Ph.D. and Stephan Kemp, Ph.D

The effect of missense (likely) pathogenic variants on ALDP stability

This image shows a hypothetical model of the adrenoleukodystrophy protein (ALDP). Individual amino acids are represented by circles. Missense pathogenic variants can affect the stability of the ALD protein. The effect of a pathogenic missense variant on ALDP stability was investigated by immunofluorescence (IF) in primary fibroblasts for more than 200 independent (non-recurring) pathogenic missense variants. The results are shown in this figure. Green circles indicate missense pathogenic variants that do not affect protein stability; red circles those that result in no detectable ALDP (see note below); orange circles represent pathogenic variants that result in reduced ALDP expression; blue circles indicate amino acid residues at which multiple missense pathogenic variants have been reported resulting in different outcomes. Black circles indicate amino acids where a pathogenic missense variants has been identified, but for which no expression data are available. Overall, >65% of all missense pathogenic variants result in reduced levels or no detectable ALDP (Kemp et al. (2001) Hum Mutat 18(6):499-515).

All other pathogenic variants (including in-frame amino acid deletions and truncations near the carboxyl terminus such as p.Gln672X) result in the absence of detectable levels of ALDP.

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To be absent or not?

In 2011, using a novel detection method based on Western blot, Zhang et al. (2011) found that residual protein is indeed present in many patient fibroblast lines harboring a missense pathogenic variant, although often below the level of detection by IF (see Table). This suggests that few newly synthesized mutant ALDP molecules fold correctly and are incorporated into the peroxisomal membrane, while most are misfolded or adopt their topology so slowly that they are rejected by the cell’s quality control machinery.

See Zhang et al. (2011) Biochem J 436(3):547-57 for experimental details.

Last modified | 2024-06-25