Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210

Abstract

BACKGROUND Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease. METHODS We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation. RESULTS Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied. CONCLUSIONS GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

“…An initial report suggests that loss of GMAP210/TRIP11 in mice alters glycosylation in the Golgi, leading to the intracellular accumulation of Perlecan in chondrocytes and resulting in a neonatal lethal form of skeletal dysplasia (57). However, recent studies suggest that GMAP210/ TRIP11 is required for efficient membrane trafficking because it regulates vesicle tethering from the ER (56,58,59).…”

The genetic aspect and morphological appearance of achondrogenesis

“…GMAP-210 moves proteins from the endoplasmic reticulum to the Golgi apparatus. 1 More over that mice lacking GMAP-210 die at birth with a pleiotropic phenotype that includes growth restriction, ventricular septal defects of the heart, omphalocele, and lung hypoplasia. 17 The Golgi apparatus is an organelle with multiple complex functions.…”

“…The result of analysis showwed that two mutations (c.202-2AG and c.589-2AG) affect intronic splice-acceptor sites and five mutations (p.R264X, p.R1028X, p.Q1160X, p.R1167X, and p.W1224X) are nonsense mutations. 1 ACG lB caused by mutations in SLC26A2 (diastrophic dysplasia sulfate transporter or DTDST) gene. The SLC26A2 gen located on 5q, hereditary by autosome recessif (AR).…”

“…13 The gen of SLC26A2 which encodes a sulfate transporter. 1 More over, mutated alleles of the SLC26A2 gene cause each of the four recessive chondrodysplasias, ie: diastrophic dysplasia (DTD), multiple epiphyseal dysplasia (MED), atelosteogenesis Type II (AO2), and ACG-1B. Result of study showed that SLC26A2 mRNA and protein immunostaining were detected in developing fetal hyaline cartilage.…”

“…Some infants, however, have lived for a while with intensive medical support. 1 The other characteristic of ACG is a lethal form of congenital dystrophy characterised by micromelia macrocephaly and a short trunk that involves both proximal and distal extremity segments. 2,3 Based on radiologic and histopathologic appearance, generally there are 3 variants of ACG, namely ACG type 1A (Houston-Harris type), ACG type 1B (ParentiFraccaro type = Fraccaro type), and ACG type 2 (LangerSaldino type).…”