Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210.

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.

Pubmed ID: 20089971 RIS Download

Mesh terms: Animals | Cell Differentiation | Cell Proliferation | Chondrocytes | Codon, Nonsense | Endoplasmic Reticulum | Genes, Recessive | Glycosylation | Golgi Apparatus | Humans | Mice | Mice, Mutant Strains | Nuclear Proteins | Osteochondrodysplasias | Phenotype | Polymorphism, Single Nucleotide | Protein Processing, Post-Translational | Sequence Analysis, DNA

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NICHD NIH HHS, Id: R01 HD036404
  • Agency: NIGMS NIH HHS, Id: GM075252
  • Agency: NICHD NIH HHS, Id: U01 HD043430
  • Agency: NICHD NIH HHS, Id: U01 HD43430
  • Agency: NICHD NIH HHS, Id: R01 HD036404-12
  • Agency: NIAMS NIH HHS, Id: R01 AR050180
  • Agency: PHS HHS, Id: A1063430
  • Agency: NICHD NIH HHS, Id: HD36404
  • Agency: NIGMS NIH HHS, Id: R01 GM075252
  • Agency: Howard Hughes Medical Institute, Id: AR050180
  • Agency: NIAMS NIH HHS, Id:

Mouse Genome Informatics (Data, Gene Annotation)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.