A common pathomechanism in GMAP-210- and LBR-related diseases

Anika Wehrle, Tomasz M. Witkos, Judith C. Schneider, Anselm Hoppmann, Sidney Behringer, Anna Köttgen, Mariet Elting, J. rgen Spranger, Martin Lowe, Ekkehart Lausch

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
JournalJCI Insight
Volume3
Issue number23
DOIs
Publication statusPublished - 2018

Cite this

Wehrle, A., Witkos, T. M., Schneider, J. C., Hoppmann, A., Behringer, S., Köttgen, A., ... Lausch, E. (2018). A common pathomechanism in GMAP-210- and LBR-related diseases. JCI Insight, 3(23). https://doi.org/10.1172/jci.insight.121150
Wehrle, Anika ; Witkos, Tomasz M. ; Schneider, Judith C. ; Hoppmann, Anselm ; Behringer, Sidney ; Köttgen, Anna ; Elting, Mariet ; Spranger, J. rgen ; Lowe, Martin ; Lausch, Ekkehart. / A common pathomechanism in GMAP-210- and LBR-related diseases. In: JCI Insight. 2018 ; Vol. 3, No. 23.
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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.",
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Wehrle, A, Witkos, TM, Schneider, JC, Hoppmann, A, Behringer, S, Köttgen, A, Elting, M, Spranger, JR, Lowe, M & Lausch, E 2018, 'A common pathomechanism in GMAP-210- and LBR-related diseases' JCI Insight, vol. 3, no. 23. https://doi.org/10.1172/jci.insight.121150

A common pathomechanism in GMAP-210- and LBR-related diseases. / Wehrle, Anika; Witkos, Tomasz M.; Schneider, Judith C.; Hoppmann, Anselm; Behringer, Sidney; Köttgen, Anna; Elting, Mariet; Spranger, J. rgen; Lowe, Martin; Lausch, Ekkehart.

In: JCI Insight, Vol. 3, No. 23, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Witkos, Tomasz M.

AU - Schneider, Judith C.

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AU - Behringer, Sidney

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AU - Elting, Mariet

AU - Spranger, J. rgen

AU - Lowe, Martin

AU - Lausch, Ekkehart

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AB - 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.

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Wehrle A, Witkos TM, Schneider JC, Hoppmann A, Behringer S, Köttgen A et al. A common pathomechanism in GMAP-210- and LBR-related diseases. JCI Insight. 2018;3(23). https://doi.org/10.1172/jci.insight.121150