Articles scientifiques

Hypomorphic mutation of TRIP11 cause odontochondrodysplasia

2019/ JCI Insight. 2019 Feb 7;4(3).


Wehrle A, Witkos TM, Unger S, Schneider J, Follit JA, Hermann J, Welting T, Fano V, Hietala M, Vatanavicharn N, Schoner K, Spranger J, Schmidts M, Zabel B, Pazour GJ, Bloch-Zupan A, Nishimura G, Superti-Furga A, Lowe M, Lausch E.


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.

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Dental Findings in Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism: A Systematic Review

2018 / English Frontiers in Physiology. 2018 Jun 19;9:701.


Hejlesen J, Underbjerg L, Gjørup H, Bloch-Zupan A, Sikjaer T, Rejnmark L, Haubek D.


Background: Dental aberrations have been mentioned in relation to non-surgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP). However, a systematic review of dental characteristics have not been performed. The present systematic review describes the dental findings in patients with Ns-HypoPT and PHP.

Methods: Studies on Ns-HypoPT and PHP reporting dental features were eligible. A systematic literature search was conducted using four bibliographic databases (Web of Science, Scopus, Pubmed, and Embase) and was limited to studies written in English. Reviews, meta-analyses and letters were excluded. Both the research and reporting of results were based on PRISMA (preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines.

Results: Of 88 studies included, nine were cross-sectional, one was a prospective cohort study, 26 were case series, and 52 were case reports. The most frequently reported findings in patients with Ns-HypoPT were enamel opacities, enamel hypoplasia, hypodontia, and eruption disturbances. In patients with PHP, enamel hypoplasia, eruption disturbance, and deviation of the root morphology were the most frequently reported findings.

Conclusion: An association between enamel hypoplasia and Ns-HypoPT and PHP is likely. The results should, however, be interpreted cautiously due to the limited number of high-quality studies. The present review confirms the need of further well-designed studies, such as large-scale studies, e.g., multicenter studies, to conclude on the reported associations between Ns-HypoPT/PHP and enamel hypoplasia.

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Genetic Evidence Supporting the Role of the Calcium Channel, CACNA1S, in Tooth Cusp and Root Patterning

2018 / English – Frontiers in Physiology, 26 September 2018, 9:1329.


Laugel-Haushalter V, Morkmued S, Stoezel C, Geoffroy V, Muller J, Boland A, Deleuze J-F, Chennen K, Pitiphat W, Dolflus H, Niederreither K, Bloch-Zupan A,  Pungchanchaikul P.


« In this study, we report a unique dominantly inherited disorganized supernumerary cusp and single root phenotype presented by 11 affected individuals belonging to 5 north-eastern Thai families. Using whole exome sequencing (WES) we identified a common single missense mutation that segregates with the phenotype in exon 6 of CACNA1S (Cav1.1) (NM_000069.2: c.[865A > G];[=] p.[Ile289Val];[=]), the Calcium Channel, Voltage-Dependent, L Type, Alpha-1s Subunit, OMIM 114208), affecting a highly conserved amino-acid isoleucine residue within the pore forming subdomain of CACNA1S protein. This is a strong genetic evidence that a voltage-dependent calcium ion channel is likely to play a role in influencing tooth morphogenesis and patterning. »

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Phenotyping of autoreactive B cells with labeled nucleosomes in 56R transgenic mice

2017 / English – Scientific Reports 2017; 7: 13232.


Gies V, Bouis D, Martin M, Pasquali JL, Martin T, Korganow AS, Soulas-Sprauel P.


« The phenotypic characterization of self-reactive B cells producing autoantibodies is one of the challenges to get further insight in the physiopathology of autoimmune diseases. We took advantage of our previously developed flow cytometry method, using labeled nucleosomes, prominent autoantigens in systemic lupus erythematosus, to analyze the phenotype of self-reactive B cells in the anti-DNA B6.56R mouse model. We showed that splenic anti-nucleosome B cells express mostly kappa light chains and harbor a marginal zone phenotype. Moreover, these autoreactive B cells fail to acquire a germinal center phenotype and are less abundant in the transitional T3 compartment. In conclusion, the direct detection of autoreactive B cells helped determine their phenotypic characteristics and provided a more direct insight into the B cell tolerance process in B6.56R mice. This method constitutes an interesting new tool to study the mechanisms of B cell tolerance breakdown in B6.56R mice crossed with autoimmune prone models. »

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Neutropenia in patients with common variable immunodeficiency: a rare event associated with severe outcome

2017 / English – Journal of Clinical Immunology 2017; 37: 715-726


Guffroy A, Mourot-Cottet R, Gérard L, Gies V, Lagresle C, Pouliet A, Nitschké P, Hanein S, Bienvenu B, Chanet V, Donadieu J, Gardembas M, Karmochkine M, Nove-Josserand R, Martin T, Poindron V, Soulas-Sprauel P, Rieux-Laucat F, Fieschi C, Oksenhendler E, André-Schmutz I, Korganow AS; DEFI study group.



Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID.


The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed.


Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0-1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35-4.4]. Most patients presented increased numbers of CD21low CD38low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA, CTLA4, and PIK3. More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process.


Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an « alarm bell » considering patients’ presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management. »

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Prothèse implantoportée en denture mixte chez l’adolescent atteint de maladies rares

2017 / Français – Réalités Cliniques 2017. Vol. 28, n°3 : pp.221-230


F. Clauss, JC. Dahlet, V. Vogt, T. Siebert, A. Bloch-Zupan, F. Obry, MC. Manière


« Les oligodonties correspondent à une anomalie du développement dentaire caractérisée par une importante variabilité clinique et doivent faire l’objet d’une prise en charge multi-disciplinaire. La mise en place précoce d’implants symphysaires sous-prothétiques en cours de croissance, à partir de l’âge de 6 ans, est indiquée et a fait l’objet d’un avis favorable de la Haute Autorité de Santé en 2006. Les principaux paramètres diagnostiques à considérer sont la sévérité du phénotype, la distribution des agénésies dentaires, la maturité squelettique et les caractéristiques morphologiques et dimensionnelles du site implantaire symphysaire. Le bilan pré-implantaire intègre un examen clinique et d’imagerie sectionnelle de type CBCT, avec reconstructions tridimensionnelles et simulation implantaire assistée par ordinateur. Les spécificités chirurgicales sont une intervention sur un os en cours de croissance et caractérisé par une hypotrophie osseuse et, dans certains cas, une hypercorticalisation, à l’origine de difficultés chirurgicales. Les mini-implants peuvent être utilisés dans les cas d’hypotrophie osseuse marquée. Un suivi rigoureux de l’ostéointegration est nécessaire, car des complications comme un enfouissement implantaire ou une modification de l’axe implantaire liée à la croissance ont été observées. Le protocole prothétique consiste en réalisation de prothèse adjointe mandibulaire implanto-stabilisée jusqu’à la fin de la croissance, évoluant en prothèse fixée supra-implantaire dès la maturité squelettique atteinte, après la mise en place d’implants supplémentaires en secteurs latéro-postérieurs mandibulaires et d’implants maxillaires. »

Evolutionary analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and previously-Identified MMP20 Mutations Causing Amelogenis Imperfecta

2017 / English – Frontiers in Physiology 2017; 8: 398


Gasse B, Prasad M, Delgado S, Huckert M, Kawczynski M, Garret-Bernardin A, Lopez-Cazaux S, Bailleul-Forestier I, Manière MC, Stoetzel C, Bloch-Zupan A, Sire JY.


« Amelogenesis imperfecta (AI) designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20) produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues), pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI. »

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Hypophosphatasie : atteintes buccale et dentaire

2017 / Français – Archives de Pédiatrie 2017


A. Bloch-Zupan, F. Vaysse


« Les anomalies dentaires sont présentes dans toutes les formes de l’hypophosphatasie (HPP), de la plus sévère à la plus modérée dite « odontohypophosphatasie ». Elles sont définies par l’âge d’apparition des premiers symptômes. Ces anomalies touchent tous les tissus minéralisés de la dent, à savoir : l’émail, la dentine, le cément et l’os alvéolaire selon un gradient proportionnel à la sévérité de la maladie. La perte précoce de dents temporaires avant l’âge de 3 ans, puis éventuellement de dents permanentes, liée à une anomalie du cément, tissu permettant l’attachement de la dent à l’os alvéolaire, est l’anomalie la plus fréquente. Cette perte des dents est un signe diagnostique très important à reconnaître. Les patients atteints d’HPP nécessitent une prise en charge bucco-dentaire adaptée en coordination avec les centres de référence et de compétence. Ces signes bucco-dentaires et leur prise en charge sont encore mal connus ; le recensement de ces anomalies et leur traitement dans un registre sont indispensables à une amélioration de la prise en charge et de la santé bucco-dentaire des patients. »

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Enamel and dental anomalies in latent-transforming growth factor beta-binding protein 3 mutant mice

2017 / English – European Journal of Oral Science 2017; 125: 8-17


Morkmued S, Hemmerle J, Mathieu E, Laugel-Haushalter V, Dabovic B, Rifkin DB, Dollé P, Niederreither K, Bloch-Zupan A.


« Latent-transforming growth factor beta-binding protein 3 (LTBP-3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor-β (TGF-β). To investigate the role of LTBP-3 in tooth formation we performed micro-computed tomography (micro-CT), histology, and scanning electron microscopy analyses of adult Ltbp3-/- mice. The Ltbp3-/- mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation-stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous-like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP-3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF-β signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3-/- mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes. »

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Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype-phenotype study

2017 / English – Clinical Genetics 2017; 92: 477-486


Tardieu C, Jung S, Niederreither K, Prasad M, Hadj-Rabia S, Philip N, Mallet A, Consolino E, Sfeir E, Noueiri B, Chassaing N, Dollfus H, Manière MC, Bloch-Zupan A, Clauss F.


« WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient’s phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient’s clinical manifestations. »