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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 4

C14 sterol reductase activity is impaired in LBR-deficient cells.

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C14 sterol reductase activity is impaired in LBR-deficient cells.
(A) LB...
(A) LBR-deficient primary fibroblasts and controls were cultured in lipid-depleted medium for 5 days, and total lipids were extracted and analyzed by gas chromatography/mass spectrometry. ACG1A_1 carries the homozygous LBR mutation described in this study; CTL_2 is representative of 3 matched wild-type controls (n = 3). Peak 1: 5β-cholestan-3α-ol (internal standard). Peak 2: cholesterol. Peak 3 (red number) was only detected in ACG1A_1 and corresponds to 8,14-cholestadien-3β-ol previously described in Greenberg dysplasia. The data are representative of 3 independent experiments (n = 3). (B) Indicated primary cells were cultured under cholesterol-restrictive growth conditions for 2 days, the medium was supplemented either with 2.5 mM methyl-β-cyclodextrin (MβCD, cholesterol depletion), or with 2.5 mM MβCD:cholesterol-saturated complexes (cholesterol replacement), and imaged by bright-field microscopy. The data are representative of 3 experiments (n = 3). (C) Growth curves of LBR-deficient cells and 3 matched controls (n = 3) in lipid-depleted medium for 9 days; 6.5 μM cholesterol was added to the medium of ACG1A_1 (ACG1A_1+CHOL) and 3 controls (CTL+CHOL). Cell numbers were determined by automated counting; data points represent the mean of triplicates values; for controls the mean of 3 pooled triplicates was determined (n = 9); error bars indicate SD. Statistical differences were assessed by 2-way ANOVA using Bonferroni’s correction for multiple comparisons; ns., not significant. *P ≤ 0.05, ****P < 0.0001.

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