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Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia

Sofie Symoens1, Aileen M Barnes2, Charlotte Gistelinck1

  • 1Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.

American Journal of Human Genetics
|September 15, 2015
PubMed

Insights

Mutations in the TAPT1 gene cause a severe skeletal and developmental disorder. This protein is crucial for centrosome and cilium function, impacting skeletal patterning and organ development.

Area of Science:

  • Genetics and Developmental Biology
  • Skeletal Biology
  • Cell Biology

Background:

  • The transmembrane anterior posterior transformation 1 (TAPT1) protein is evolutionarily conserved and implicated in skeletal patterning.
  • The precise cellular function of TAPT1 has remained largely unknown.
  • Clinical data suggests a link between TAPT1 mutations and a complex congenital syndrome.

Purpose of the Study:

  • To elucidate the cellular function of TAPT1.
  • To characterize the molecular basis of a congenital syndrome associated with TAPT1 mutations.
  • To investigate the role of TAPT1 in skeletal development and ciliopathies.

Main Methods:

  • Human genetic analysis of patients with a novel congenital syndrome.
  • Cellular localization studies of wild-type and mutant TAPT1.
  • Zebrafish (tapt1b) knockdown model to study developmental effects.
  • Analysis of Golgi morphology, intracellular trafficking, and primary cilium formation.

Main Results:

  • TAPT1 mutations cause a lethal skeletal dysplasia syndrome with fetal lethality, hypomineralization, fractures, and multiple organ anomalies.
  • Wild-type TAPT1 localizes to the centrosome/ciliary basal body; mutant TAPT1 mislocalizes to the cytoplasm.
  • Defective TAPT1 disrupts Golgi trafficking and primary cilium formation.
  • Zebrafish tapt1b knockdown results in craniofacial cartilage defects and delayed ossification due to aberrant cranial neural crest cell differentiation.

Conclusions:

  • TAPT1 is essential for normal skeletal development, organogenesis, and ciliogenesis.
  • TAPT1 mutations disrupt centrosome/cilium function, leading to a complex ciliopathy and skeletal dysplasia syndrome.
  • TAPT1 plays a critical role in cranial neural crest cell differentiation, impacting craniofacial development.

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