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

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 1

LBR mutations cause a phenocopy of achondrogenesis 1A (ACG1A).

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LBR mutations cause a phenocopy of achondrogenesis 1A (ACG1A). (A) Clin...
(A) Clinical photographs of the fetus at 21 weeks and 5 days, presenting with hydrops, shortened extremities, protruding abdomen, and short trunk. (B) Radiographs in frontal and lateral view show delayed ossification of spine and pelvis. Note the barrel-shaped thorax with horizontally oriented ribs and the extremely shortened long bones. (C) Sanger sequencing of genomic DNA demonstrates a homozygous mutation of the LBR gene (c.[366+1g>t];[366+1g>t]) that abrogates the splice donor site of exon 3. The abridged pedigree above shows cosegregation of the LBR mutation; *termination of pregnancy (TOP) because of cardiac malformation. (D) Exon-spanning reverse transcription PCR analysis of LBR (35 cycles) using cDNA derived from patient and matched control fibroblasts (CTL1, 2). Below: Schematic representation and electropherogram of the amplified/sequenced region and the splice mutation of LBR (indicated by a red arrow) that causes a partial deletion of exon 3, leading to a frameshift and premature termination codon in the open reading frame of LBR (p.E112Sfs*39). Gray horizontal arrows indicate the relative position of primers (not to scale).