Defects in TAPT1, involved in axial skeletal patterning, cause a complex lethal recessive disorder of skeletal development. S. Symoens1, A. Barnes2, C. Ghistelinck1, F. Malfait1, K. Vleminckx1, B. Guillemyn1, D. Syx1, W. Steyaert1, E. Parthoens3, M. Biervliet4, G. Gillessen-Kaesbach5, J. De Backer1, A. Willaert1, H. P. Bächinger6,7, A. De Paepe1, J. C. Marini2, P. J. Coucke1 1) Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium; 2) Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD, United States; 3) Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; 4) Center for Medical Genetics, Brussels University Hospital, Brussels, Belgium; 5) Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany; 6) Research Department, Shriners Hospitals for Children, Portland, OR, United States; 7) Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, United States.

   TAPT1 encodes the evolutionary highly conserved Transmembrane Anterior Posterior Transformation-1 protein. ENU mutagenesis of TAPT1 results in embryonic lethality of murine homozygotes, with posterior to anterior transformations of thoracic and lumbar vertebrae. The mechanism by which this ubiquitously expressed protein causes a specific patterning defect and lethality is unknown. We describe a Moroccan family with three lethal fetuses affected with fractures of ribs and long bones, undermineralized skull and axial skeleton, hydramnios with ascites and dilated ventricles. Because of the occurrence of multiple fractures and undermineralized skeleton, a clinical diagnosis of lethal autosomal recessive Osteogenesis Imperfecta was suggested. Although type I collagen folding was slightly delayed, causing mild overmodification of type I collagen, thorough molecular analysis of all known OI genes did not detect a causal mutation. We combined homozygosity mapping with exome sequencing, which identified a homozygous c.1108-1GC mutation in TAPT1, causing in-frame skipping of exon 10. A second homozygous TAPT1 missense mutation in exon 9 (c.1058AT, p.(Asp353Val)) was identified by direct sequencing in a complex Syrian pedigree with three lethal fetuses with fractures and multiple congenital anomalies of brain, face, heart and lungs. Immunocytochemical staining of dermal fibroblasts revealed co-localization of TAPT1 with the centrosomal protein -tubulin, while co-staining with acetylated tubulin detected that TAPT1 forms a pocket in which the primary cilium is inserted. Increased TAPT1 expression was observed during cilium formation. Moreover, we showed in patients dermal fibroblasts that primary cilium formation is severely disturbed. A zebrafish tapt1b-morpholino-approach revealed severe cartilage malformation and a delay in bone formation. Our results show that defects in TAPT1 underlie a novel autosomal recessive disorder, which is characterized by multiple fractures in utero, generalized undermineralization of the skeleton, microbrachycephaly, ascites and pleural effusion. We also prove that TAPT1 is a centrosomal protein that is of crucial importance for proper cilium formation, thereby suggesting that this disorder is a novel ciliopathy.

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