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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 6

Abnormal vesiculation at the Golgi apparatus is a common cellular phenotype in achondrogenesis 1A (ACG1A).

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Abnormal vesiculation at the Golgi apparatus is a common cellular phenot...
(A) Transmission electron 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_3 is representative of 3 matched wild-type controls (n = 3). Red arrowheads mark large vesicular profiles, blue arrowheads normal Golgi stacks in ACG1A_1 and control cells. Scale bar: 500 nm. (B) Quantification of cells with abnormal vesiculation, defined as peri-Golgi circular profiles with a diameter of >100 nm (red bars) compared with cells with normal Golgi morphology (blue bars); the y axis shows the percentage of respective phenotypes, and the individual cell counts are indicated above the bars. The significance of differences in the number of cells with large vesicular profiles was compared using a χ2 test; **P < 0.01; ***P < 0.001.

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