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A common pathomechanism in GMAP-210– and LBR-related diseases
Anika Wehrle, … , Martin Lowe, Ekkehart Lausch
Anika Wehrle, … , Martin Lowe, Ekkehart Lausch
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e121150. https://doi.org/10.1172/jci.insight.121150.
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Research Article Cell biology Genetics

A common pathomechanism in GMAP-210– and LBR-related diseases

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Abstract

Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP-210– and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients’ cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210– and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus.

Authors

Anika Wehrle, Tomasz M. Witkos, Judith C. Schneider, Anselm Hoppmann, Sidney Behringer, Anna Köttgen, Mariet Elting, Jürgen Spranger, Martin Lowe, Ekkehart Lausch

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Figure 7

Reduced secretory trafficking and defective glycoprocessing in achondrogenesis 1A (ACG1A).

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Reduced secretory trafficking and defective glycoprocessing in achondrog...
Patient and control fibroblasts were starved for 1 hour in methionine- and cysteine-free medium and pulsed for 20 minutes with fresh starvation medium containing 50 μCi/ml [35S]methionine and [35S]cysteine protein-labeling mix. Cells were chased in medium containing unlabeled methionine and cysteine for 0, 30, or 60 minutes. Proteins secreted to the medium were precipitated and lysed. (A) Radiolabeled secreted proteins in trichloroacetic acid precipitates were subjected to denaturing gel electrophoresis and visualized by phosphorimaging. ACG1A_1 carries the homozygous LBR mutation described in this study, ACG1A_2 bears biallelic mutations of TRIP11; CTL_2 and 3 are matched wild-type controls (n = 2). (B) Ratio of secreted-to-total proteins at the indicated time points. Data represent mean ± SEM of 3 independent experiments (n = 3; one-way ANOVA with Dunnett’s multiple comparisons test). *P ≤ 0.05, **P < 0.01. (C) Immunoblot analyses of LAMP1, and (D) LAMP2 proteins in whole-cell lysates of ACG1A patient and control fibroblasts. Membranes were overexposed to detect weaker signals. Low-molecular-weight intermediate glycosylation products of LAMP1 in ACG1A_1 are marked by a red asterisk. Similar, but faster migrating protein species are visible in ACG1A_3 (red asterisk). Non-glycosylated forms are present at very low steady state levels in CTL_3 and ACG1A_2 cells. As for LAMP1, the mature LAMP2 proteins in ACG1A run at a lower molecular weight range than in controls. An intermediate product is present in ACG1A_1 cells (~60 kDa, red asterisk).

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