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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 3

Loss of LBR or GMAP-210 in achondrogenesis 1A (ACG1A) patient–derived primary cells.

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Loss of LBR or GMAP-210 in achondrogenesis 1A (ACG1A) patient–derived pr...
Immunofluorescence microscopy of patient and control fibroblasts; ACG1A_1 carries the homozygous LBR mutation described in this study, ACG1A_2 and 3 bear biallelic mutations of TRIP11; CTL_1 and 3 are representative matched wild-type controls. Cells were grown on coverslips, fixed, and costained with (A) LBR- and lamin B–specific antibodies, or (B) using antibodies directed against GMAP-210 and the cis-Golgi marker GM130. Nuclear DNA was stained with Hoechst 33342 dye. White lines indicate where red, green, and blue (RGB) fluorescence was quantified; RGB profile plots of the sections are shown on the right. Scale bars: 10 μm.

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