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

Abstract

The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells.

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

“…TAPT1 encodes transmembrane anterior posterior transformation 1 protein that was found by Symoens et al to be mutated in two families with osteogenesis imperfect alike skeletal dysplasia (Symoens et al 2015). On the other hand, the family we describe in which cataract maps to a single locus in which a homozygous splicing TAPT1 mutation was identified did not have any evidence of skeletal involvement.…”

Whole-Genome Methylation Analysis Reveals Epigenetic Variation in Cloned and Donor Pigs

“…ITPR2 is an important regulator of calcium-channel activity, which is the basis of animal fertilization and embryonic development (Kuroda et al, 1999;Miao and Williams, 2012). TAPT1 defects can lead to fatal chondrodysplasia of the fetus (Symoens et al, 2015) and CALML5 regulates epidermal differentiation by binding to stratifin (Sun et al, 2015). Differences in the expression of these genes may explain the delayed first calving age and the fewer offspring of the CP.…”

Prenatal diagnosis of skeletal dysplasias using a targeted skeletal gene panel

“…Recent advances in molecular technology have improved the ability to make diagnoses in skeletal dysplasia such that the molecular basis has been determined in approximately 70% of the 436 skeletal disorders . Technological breakthroughs, such as next‐generation sequencing (NGS), have given clinicians and researchers a number of tools to help make a diagnosis when a condition with a potentially heterogeneous aetiology is suspected .…”