Hypomorphic mutations of TRIP11 cause odontochondrodysplasia
Anika Wehrle, Tomasz M. Witkos, Sheila Unger, Judith Schneider, John A. Follit, Johannes Hermann, Tim Welting, Virginia Fano, Marja Hietala, Nithiwat Vatanavicharn, Katharina Schoner, Jürgen Spranger, Miriam Schmidts, Bernhard Zabel, Gregory J. Pazour, Agnes Bloch-Zupan, Gen Nishimura, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch
Anika Wehrle, Tomasz M. Witkos, Sheila Unger, Judith Schneider, John A. Follit, Johannes Hermann, Tim Welting, Virginia Fano, Marja Hietala, Nithiwat Vatanavicharn, Katharina Schoner, Jürgen Spranger, Miriam Schmidts, Bernhard Zabel, Gregory J. Pazour, Agnes Bloch-Zupan, Gen Nishimura, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch
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Research Article Bone biology Genetics

Hypomorphic mutations of TRIP11 cause odontochondrodysplasia

Abstract

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus.

Authors

Anika Wehrle, Tomasz M. Witkos, Sheila Unger, Judith Schneider, John A. Follit, Johannes Hermann, Tim Welting, Virginia Fano, Marja Hietala, Nithiwat Vatanavicharn, Katharina Schoner, Jürgen Spranger, Miriam Schmidts, Bernhard Zabel, Gregory J. Pazour, Agnes Bloch-Zupan, Gen Nishimura, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch

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Figure 2

Recessive mutations in TRIP11 cause achondrogenesis type 1A (ACG1A) and odontochondrodysplasia (ODCD).

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Recessive mutations in TRIP11 cause achondrogenesis type 1A (ACG1A) and ...
(A) Diagram of the human TRIP11 locus and relative size of its 21 coding exons. Lines indicate mutations identified in ACG1A (top) and ODCD (bottom) pointing to their locations within the exons. Nonsense and frameshift mutations are depicted in black, splice mutations in blue, and mutations shared by ODCD and ACG1A in red; recurrent mutations are underlined. (B) Semiquantitative reverse transcription PCR of TRIP11 using cDNA of control fibroblasts (CTL1 to -4), fibroblasts of ACG1A cases A1 and A2, and ODCD cases 6, 3, and 10. TBP was used for normalization. (C) Quantitative PCR (qPCR) analysis of TRIP11 using cDNA derived from control and patients’ fibroblasts. TBP and HPRT were used for normalization. For qPCR results, the average value of the controls (n = 12) was set to 1. For TRIP11-mutant cells, horizontal lines represent the mean of quadruplicates (n = 4); error bars indicate SD. Statistical differences were assessed by 2-way ANOVA with Bonferroni’s post hoc test; ****P < 0.0001. –RT, without reverse transcriptase.