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

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 2

Analysis of LBR and TRIP11 mRNA and protein expression in achondrogenesis 1A (ACG1A) patient–derived primary cells.

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Analysis of LBR and TRIP11 mRNA and protein expression in achondrogenesi...
Semiquantitative reverse transcription PCR (left, 25 cycles), and quantitative real-time PCR (RT-qPCR) analysis (right) of (A) LBR, and (B) TRIP11 of cDNA derived from patient and control primary fibroblasts. ACG1A_1 carries the homozygous LBR mutation described in this study, ACG1A_2 and 3 bear biallelic mutations of TRIP11; CTL_1 to 3 are matched wild-type controls. TBP was used for normalization; the same agarose gel is shown in A and B, which are representative of 3 independent experiments (N = 3). For RT-qPCR results, the average value of the controls was set to 1 (n = 12). Horizontal lines represent the mean of quadruplicates (n = 4), error bars indicate SD. Statistical differences were assessed by 1-way ANOVA using Bonferroni’s correction for multiple comparisons; ns., not significant. ****P < 0.0001. Immunoblots of (C) LBR and (D) GMAP-210 protein in whole-cell lysates of patients and controls; GAPDH staining indicates total protein loading and was used for normalization in quantitative signal analysis (right). Horizontal lines represent the mean of triplicate quantitative blot signal analyses (n = 3), error bars indicate SD. Statistical differences were assessed by 1-way ANOVA using Bonferroni’s correction for multiple comparisons; ns., not significant. *P ≤ 0.05, ***P < 0.001. See complete unedited blots in the supplemental material.