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Achondrogenesis type 1A (ACG1A) is an autosomal recessive neonatal lethal skeletal disorder. Newborns affected with Achondrogenesis type 1A have severe shortening of all bones  and also feature absent mineralization in the skull and the vertebral column.

We identified mutations in the gene TRIP11 as the cause of ACG1A. The TRIP11 gene encodes the protein GMAP210. This protein is involved in the trafficking of proteins inside a cell. Most proteins are synthesized in the Endoplasmic reticulum, which can be considered as the cell’s protein factory. After their synthesis these proteins need to be transported to the regions in or outside the cell where their function is required. This process is called protein trafficking. A central player in protein trafficking is the Golgi apparatus, which can be considered as the cell’s postal office.  Proteins leave the Endoplasmic reticulum in so called transport vesicles. These vesicles are transported to what is called the cis-side of the Golgi apparatus where the proteins are released in the Golgi apparatus. In the Golgi apparatus the proteins will be sorted into specific vesicles destined for specific locations inside or outside the cell. These vesicles leave the Golgi apparatus on the so-called trans side, opposite to the cis-side. The protein GMAP210 can be found at the cis side of the Golgi apparatus and most likely functions as a tethering factor that captures transport vesicles arriving from the Endoplasmic reticulum and helps with the fusion of these vesicles with the cis-side of the Golgi apparatus. In the absence of GMAP210 protein trafficking from the Endoplasmic reticulum is impeded. In the cell’s of the skeleton (the cartilage producing chondrocyte and the bone producing osteoblasts) this disturbance in protein trafficking results in the accumulation of proteins inside the Endoplasmic reticulum and subsequently cell death.

Among the questions we want to answer are:

  1. Why does absence of GMAP210, which is present in every cell of the body, so severely affect the cells of the skeleton?
  2. Does GMAP210 tether vesicles with proteins that are only produced in chondrocytes and osteoblasts?
  3. With which other proteins does GMAP210 interact in its role in protein trafficking?
  4. Do all ACG1A patients have mutations in GMAP210 or can mutations in GMAP210 interacting proteins cause the same disease?

Interested in participating?

We welcome individuals and families who are affected by AMDM to participate in our research by contacting us.

To improve our ability to diagnose ACG1A, we are seeking blood samples from patients with ACG1A and their unaffected relatives. 

To better understand how GMAP210 functions within the body, we are seeking skin fibroblasts and/or skeletal tissue that can be recovered from patients with ACG1A at the time of a medically-indicated procedure.

Studying the consequences of ACG1A at the cellular, biophysical, and protein levels may help in furthering the development of new therapeutic strategies.

Physicians seeking assistance in making a diagnosis of ACG1A or other forms of skeletal dysplasia are also welcome to contact us.