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Functional Mutation Analysis Provides Evidence for a Role of REEP 1 in Lipid Droplet Biology
Author(s) -
Falk Julia,
Rohde Magdalena,
Bekhite Mohamed M.,
Neugebauer Sophie,
Hemmerich Peter,
Kiehntopf Michael,
Deufel Thomas,
Hübner Christian A.,
Beetz Christian
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22521
Subject(s) - biology , endoplasmic reticulum , missense mutation , hereditary spastic paraplegia , unfolded protein response , mutation , gene knockdown , gene isoform , phenotype , genetics , microbiology and biotechnology , gene
Hereditary axonopathies are frequently caused by mutations in proteins that reside in the endoplasmic reticulum ( ER ). Which of the many ER functions are pathologically relevant, however, remains to be determined. REEP 1 is an ER protein mutated in hereditary spastic paraplegia ( HSP ) and hereditary motor neuropathy ( HMN ). We found that HSP ‐associated missense variants at the N ‐terminus of REEP 1 abolish ER targeting, whereas two more central variants are either rare benign SNP s or confer pathogenicity via a different mechanism. The mis‐targeted variants accumulate at lipid droplets ( LD s). N ‐terminal tagging, deletion of the N ‐terminus, and expression of a minor REEP 1 isoform had the same effect. We also confirmed an increase in LD size upon cooverexpression of atlastins and REEP 1. Neither wild‐type REEP 1, LD ‐targeted HSP variants, nor a non‐ LD ‐targeted HMN variant reproduced this effect when expressed alone. We conclude that the N ‐terminus of REEP 1 is necessary for proper targeting to and/or retention in the ER . The protein's potential to also associate with LD s corroborates a synergistic effect with atlastins on LD size. Interestingly, LD size is also altered upon knockdown of seipin, mutations of which also cause HSP and HMN . Regulation of LD s may thus be an ER function critical for long‐term axonal maintenance.