Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4.

ABSTRACT: Genetic variation in the membrane trafficking adapter protein complex 4 (AP-4) can result in pathogenic neurological phenotypes including microencephaly, spastic paraplegias, epilepsy, and other developmental defects. We lack molecular mechanisms responsible for impaired AP-4 function arising from genetic variation, because AP-4 remains poorly understood structurally. Here, we analyze patterns of AP-4 genetic evolution and conservation to identify regions that are likely important for function and thus more susceptible to pathogenic variation. We map known variants onto an AP-4 homology model and predict the likelihood of pathogenic variation at a given location on the structure of AP-4. We find significant clustering of likely pathogenic variants located at the interface between the β4 an

SUBMITTER: Gadbery JE 

PROVIDER: S-EPMC7255511 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature