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.
Highlights
Recessive loss-of-function mutations in the lamin B receptor (LBR) and the thyroid hormone receptor interactor 11 (TRIP11) genes cause lethal human chondrodysplasias with distinct phenotypes [1, 2]
Our results show that loss-of-function mutations of LBR had no apparent effect on GMAP-210, thereby excluding the possibility that the associated ACG1A phenotype is due to a downregulation or mislocalization of GMAP-210
GRBGD is considered to be the null phenotype of LBR mutations, whereas variants that are predicted to retain residual functions cause milder skeletal phenotypes (Supplemental Table 1) [6, 7]
Summary
Recessive loss-of-function mutations in the lamin B receptor (LBR) and the thyroid hormone receptor interactor 11 (TRIP11) genes cause lethal human chondrodysplasias with distinct phenotypes [1, 2]. Compound heterozygous LBR mutations were recently identified in PHA cases affected by mild skeletal anomalies and short stature [6, 7]. Biallelic loss-of-function mutations of LBR fatally disrupt skeletal development, resulting in the clearly recognizable clinical entity of hydrops-ectopic-calcification-moth-eaten (HEM), known as Greenberg dysplasia (GRBGD, MIM 215140) [9]. GRBGD is currently included in the chondrodysplasia punctata (CDP) group of diseases, which covers heterogeneous metabolic skeletal dysplasias with overlapping clinical features [2]. Similar to GRBGD, enzymes of cholesterol metabolism are deficient in a number of CDP types.
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