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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 9

LBR and GMAP-210 deficiency impair vesicular transport in the early secretory pathway and cause defective glycoprocessing by the Golgi apparatus.

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LBR and GMAP-210 deficiency impair vesicular transport in the early secr...
Left: Wild-type cells. Middle: LBR localizes to the nuclear envelope and to the endoplasmic reticulum (ER), functioning in lamin/chromatin-binding and as a sterol reductase. Loss of LBR impairs de novo synthesis of cholesterol and causes disruption of cholesterol-sensitive ER/Golgi trafficking, resulting in defective posttranslational glycan processing and Golgi vesiculation. Right: GMAP-210 is a tether for transport vesicles at the cis-Golgi and is required to maintain Golgi structure. Loss of GMAP-210 also leads to disruption of ER/Golgi trafficking, impaired glycan processing, and Golgi vesiculation. Thus, both lesions converge on Golgi organization and function in achondrogenesis 1A (ACG1A).

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