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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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14 June 2017|Scientific articles|

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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1 May 2017|Scientific articles|

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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1 February 2017|Scientific articles|

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.”

20 January 2017|Scientific articles|

Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

2017 / English – Frontiers in Physiology 2017


S. Morkmued, V. Laugel-Haushalter, E. Mathieu, B. Schuhbaur, J. Hemmerlé, P. Dollé, A. Bloch-Zupan, K. Niederreither


“Abnormalities of enamel matrix proteins deposition, mineralization, or degradation during tooth development are responsible for a spectrum of either genetic diseases termed Amelogenesis imperfecta or acquired enamel defects. To assess if environmental/nutritional factors can exacerbate enamel defects, we investigated the role of the active form of vitamin A, retinoic acid (RA). Robust expression of RA-degrading enzymes Cyp26b1 and Cyp26c1 in developing murine teeth suggested RA excess would reduce tooth hard tissue mineralization, adversely affecting enamel. We employed a protocol where RA was supplied to pregnant mice as a food supplement, at a concentration estimated to result in moderate elevations in serum RA levels. This supplementation led to severe enamel defects in adult mice born from pregnant dams, with most severe alterations observed for treatments from embryonic day (E)12.5 to E16.5. We identified the enamel matrix proteins enamelin (Enam), ameloblastin (Ambn), and odontogenic ameloblast-associated protein (Odam) as target genes affected by excess RA, exhibiting mRNA reductions of over 20-fold in lower incisors at E16.5. RA treatments also affected bone formation, reducing mineralization. Accordingly, craniofacial ossification was drastically reduced after 2 days of treatment (E14.5). Massive RNA-sequencing (RNA-seq) was performed on E14.5 and E16.5 lower incisors. Reductions in Runx2 (a key transcriptional regulator of bone and enamel differentiation) and its targets were observed at E14.5 in RA-exposed embryos. RNA-seq analysis further indicated that bone growth factors, extracellular matrix, and calcium homeostasis were perturbed. Genes mutated in human AI (ENAM, AMBN, AMELX, AMTN, KLK4) were reduced in expression at E16.5. Our observations support a model in which elevated RA signaling at fetal stages affects dental cell lineages. Thereafter enamel protein production is impaired, leading to permanent enamel alterations.”

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6 January 2017|Scientific articles|

SLC13A5 is the second gene associated with Kohlschütter–Tönz syndrome

2017 / English – Journal of Medical Genetics 2017; 54: 54-62


Schossig A, Bloch-Zupan A, Lussi A, Wolf NI, Raskin S, Cohen M, Giuliano F, Jurgens J, Krabichler B, Koolen DA, de Macena Sobreira NL, Maurer E, Muller-Bolla M, Penzien J, Zschocke J, Kapferer-Seebacher I.




Kohlschütter-Tönz syndrome (KTZS) is a rare autosomal-recessive disease characterised by epileptic encephalopathy, intellectual disability and amelogenesis imperfecta (AI). It is frequently caused by biallelic mutations in ROGDI. Here, we report on individuals with ROGDI-negative KTZS carrying biallelic SLC13A5 mutations.


In the present cohort study, nine individuals from four families with the clinical diagnosis of KTZS and absence of ROGDI mutations as well as one patient with unexplained epileptic encephalopathy were investigated by clinical and dental evaluation, parametric linkage analysis (one family), and exome and/or Sanger sequencing. Dental histological investigations were performed on teeth from individuals with SLC13A5-associated and ROGDI-associated KTZS.


Biallelic mutations in SLC13A5 were identified in 10 affected individuals. Epileptic encephalopathy usually presents in the neonatal and (less frequently) early infantile period. Yellowish to orange discolouration of both deciduous and permanent teeth, as well as wide interdental spaces and abnormal crown forms are major clinical signs of individuals with biallelic SLC13A5 mutations. Histological dental investigations confirmed the clinical diagnosis of hypoplastic AI. In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI.


We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI. Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene. Hypersensitivity of teeth as well as high caries risk requires individual dental prophylaxis and attentive dental management.”

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1 January 2017|Scientific articles|

Hypophosphatasia: diagnosis and clinical signs – a dental surgeon perspective

2016 / English – International Journal of Paediatric Dentistry 2016; 26: 426–438


Agnès Bloch-Zupan


Background. Hypophosphatasia (HPP) is a rareinherited metabolic disease in which mutations in the ALPL gene (encoding tissue-nonspecific alkaline phosphatase) result in varying degrees of enzyme deficiency. HPP manifests in a spectrum of symptoms, including early primary tooth loss (root intact) and alveolar bone mineralisation defects.
Objective. To provide an overview of HPP for dental professionals to help recognise and differentially diagnose patients for appropriate referral to a specialist team.
Methods. A non-systematic review of publications on HPP was performed.”

26 November 2016|Scientific articles|

Photos de la Fête de la Science 2016

RARENET était présent à la médiathèque Malraux de Strasbourg du 13 au 15 octobre pour la Fête de la Science et a accueilli près de 300 visiteurs !

18 November 2016|Events|

Symposium Décembre 2016

Un premier symposium à Strasbourg en décembre

Il reste encore quelques jours pour s’inscrire au premier symposium consacré aux maladies auto-immunes rares et vascularites et aux agénésies dentaires multiples en présence de conférenciers internationaux. Il se déroulera les 7 et 8 décembre 2016 dans les locaux de la Faculté de Chirurgie Dentaire de l’Université de Strasbourg.

Cette rencontre est aussi l’occasion de fêter les 10 ans du Centre de référence pour les Manifestations Odontologiques des Maladies Rares de Strasbourg, coordonné par le Professeur Marie-Cécile Manière et le lancement officiel du projet RARENET.

RARENET innove en proposant aux enseignants, chercheurs et praticiens, médecins et chirurgiens-dentistes des temps communs d’échanges autour des manifestations bucco-dentaires des maladies rares et des maladies auto-immunes rares

Renseignements et inscriptions : – + 33(0)3 68 85 39 19

18 November 2016|Events|

L’implantologie dans les cas de dysplasie ectodermique

2016 / Français – ROS – Septembre 2016 – Tome 45 – N° 3


F. Clauss, F. Obry, S. Jung, JC. Dahlet, E. Waltmann, A. Bloch-Zupan, V. Vogt, MC. Manière


“Les thérapeutiques implantaires précoces des patients atteints de dysplasie ectodermique présentent des spécificités chirurgicales, anatomiques et physiologiques en rapport avec le phénotype osseux et la croissance. Le degré de maturité squelettique et psychique, le phénotype dentaire et les antécédents prothétiques sont des éléments diagnostiques essentiels. L’imagerie sectionnelle CBCT pré-opératoire est essentielle dans ce contexte et permet une évaluation qualitative et mensurative du support osseux symphysaire. En fonction des observations cliniques et tomographiques, le praticien s’orientera vers la mise en place d’implants standards de faible dimension ou de mini-implants, dans les cas d’anodontie ou d’hypotrophie osseuse très marquée. La différence de taille entre ces deux approches est la nécessité de dépose des miniimplants à la fin de la croissance et leur remplacement par des implants ostéointégrés standards. Des études multi-centriques, un recul clinique et radiologique plus important sont nécessaires pour mieux étudier le comportement de ces mini-implants à long terme. Un suivi rigoureux de l’ostéointégration et un renouvellement prothétique régulier de la prothèse adjointe supra-implantaire, en fonction du rythme de croissance des bases osseuses, sont nécessaires.”

1 September 2016|Scientific articles|