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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 8

LBR sterol reductase activity restores glycan processing in LBR-deficient cells.

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LBR sterol reductase activity restores glycan processing in LBR-deficien...
(A) Immunofluorescence microscopy of ACG1A_1 fibroblasts stained with LBR-specific antibodies; ACG1A_1 carries the homozygous LBR-null mutation. Cells were either not transfected (parental) or transiently transfected with vectors overexpressing the indicated LBR variants; the Greenberg dysplasia–associated p.N547D and p.R583Q missense mutations specifically abrogate C14 sterol reductase activity but do not alter the chromatin/lamin-binding properties of the respective LBR protein. WT, wild type. Scale bar: 10 μm. (B) ACG1A_1 cells were either electroporated without plasmid (mock), with empty vector (vector), or with expression constructs encoding the indicated LBR proteins. Whole-cell protein lysates of nontransfected wild-type controls (CTL) and ACG1A_1 transfectants were obtained 96 hours after electroporation and analyzed by Western blotting with LBR- and LAMP2-specific antibodies. GAPDH immunostaining of the stripped membrane indicates total protein loading. Fast-migrating nonglycosylated LAMP2 is highlighted by a pink asterisk at approximately 30 kDa; intermediate glycosylation products are marked by a red asterisk at approximately 65 kDa. In ACG1A_1 cells overexpressing wild-type LBR, nonglycosylated LAMP2 and intermediate glycosylation products are not detectable and mature LAMP2 has a similar molecular weight to that in nontransfected wild-type fibroblasts with an additional intermediate band at approximately 85 kDa (blue asterisk), likely corresponding to a more highly modified species than that seen upon LBR deficiency, although not fully mature. Note that a higher protein load of nontransfected wild-type fibroblasts was used to visualize the normal electrophoretic mobility pattern of LAMP2 species.

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