Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with
            <i>MMP20</i>

Nikolopoulos, Georgios; Smith, Claire E. L.; Poulter, James A.; Murillo, Gina; Silva, Sandra; Lamb, Teresa M.; Berry, Ian; Brown, Catriona J.; Day, Peter; Soldani, Francesca; Al-Bahlani, Suhaila; Harris, Sarah A.; O’Connell, Mary J.; Inglehearn, Chris F.; Mighell, Alan J.

doi:10.1002/humu.24187

Cited by 4 publications

(5 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As KLK4 and MMP20 seem to work in a collaborative manner, it is not surprising to note a similar dental phenotype in individuals with KLK4 (Hart et al, 2004) or MMP20 (Kim et al, 2005b) variants. We found 16 individuals (Supplementary Table S3; Supplementary Figure S2K) presenting with hypomature AI both in their primary and permanent dentitions; their phenotypes are similar to the ones described in the literature and associated with MMP20 recessive inheritance (Kim et al, 2005b;Ozdemir et al, 2005b;Papagerakis et al, 2008;Lee et al, 2010;Gasse et al, 2013;Kim et al, 2017;Wang et al, 2020;Nikolopoulos et al, 2021). Individuals 11.1,11.2,11.3 and 11.4 have compound heterozygous variants in MMP20 gene (Supplementary Figures S3.20,3.21,3.22).…”

Section: Mmp20supporting

confidence: 76%

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Bloch-Zupan,

Rey,

Jimenez-Armijo

et al. 2023

Front. Physiol.

View full text Add to dashboard Cite

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.

show abstract

Section: Mmp20supporting

confidence: 76%

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Bloch-Zupan,

Rey,

Jimenez-Armijo

et al. 2023

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…The younger brother was heterozygous for the LAMA3 variant but inherited no MMP20 mutations. These 2 MMP20 mutations have never been reported in AI kindreds, bringing the number of known pathogenic MMP20 variants to 24 (Nikolopoulos et al, 2021; Wang et al, 2020). Phenotypically, it has been demonstrated that biallelic MMP20 mutations can cause a wide spectrum of enamel malformations, ranging from hypoplastic to hypomaturation defects (Wang et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

Section: Family 4 (Ng_0078532:g265216g > C)mentioning

confidence: 99%

Phenotypic variability in LAMA3‐associated amelogenesis imperfecta

et al. 2022

View full text Add to dashboard Cite

ObjectiveAmelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha‐3) encodes a critical protein component of the basement membrane (laminin‐332). Individuals carrying heterozygous LAMA3 mutations have previously been shown to have localized enamel defects. This study aimed to define clinical phenotypes and to discern the genetic etiology for four AI kindreds.Materials and MethodsWhole‐exome analyses were conducted to search for sequence variants associated with the disorder, and micro‐computed tomography (μCT) to characterize the enamel defects.ResultsThe predominant enamel phenotype was generalized thin enamel with defective pits and grooves. Horizonal bands of hypoplastic enamel with chalky‐white discoloration and enamel hypomineralization were also observed and demonstrated by μCT analyses of affected teeth. Four disease‐causing LAMA3 mutations (NM_198129.4:c.3712dup; c.5891dup; c.7367del; c.9400G > C) were identified. Compound heterozygous MMP20 mutations (NM_004771.4:c.539A > G; c.692C > T) were also found in one proband with more severe enamel defects, suggesting a mutational synergism on disease phenotypes. Further analyses of the AI‐causing mutations suggested that both α3A (short) and α3B (long) isoforms of LAMA3 are essential for enamel formation.ConclusionsHeterozygous LAMA3 mutations can cause generalized enamel defects (AI1A) with variable expressivity. Laminin‐332 is critical not only for appositional growth but also enamel maturation.

show abstract

“…Mutations in the gene encoding MMP-20 have been proven to cause disorders in proper enamel development such as amelogenesis imperfecta. The enamel of patients with this disorder is characterized by a soft and rough surface with foci of pigmentation [ 65 , 66 ]. Additionally, such patients are at risk of more rapid dental caries and earlier tooth loss [ 67 ].…”

Section: Metalloproteinases and Their Role In The Human Body With Spe...mentioning

confidence: 99%

Importance of Metalloproteinase 8 (MMP-8) in the Diagnosis of Periodontitis

Zalewska,

Ławicka,

Grygorczuk

et al. 2024

IJMS

View full text Add to dashboard Cite

Periodontitis is a complex condition. Left untreated, it leads to tooth loss and the need for prosthetic treatment. The incidence of periodontitis is steadily increasing, so new methods are being sought to aid in the diagnosis of the disease. Among the methods postulated is the determination of concentrations of bioactive compounds which include extracellular matrix metalloproteinases (MMPs). These enzymes are present in various structural elements of the stomatognathic system. The most promising enzyme of this group appears to be metalloproteinase 8 (MMP-8). MMP-8 assays are performed in gingival fluid or saliva, and MMP-8 levels have been shown to be higher in patients with periodontitis compared to healthy subjects and correlated with some clinical parameters of the condition and the severity of the disease. In addition, the preliminary usefulness of this enzyme in evaluating the effectiveness of periodontal treatment and doxycycline therapy has been demonstrated. Determination of the active form of MMP-8 (aMMP-8) in oral rinse fluid using off-the-shelf assays shows the highest potential. Despite reports about aMMP-8 and promising data on the role of MMP-8 in periodontal diagnosis, a clear determination of the usefulness of this enzyme requires further research.

show abstract

Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20

Cited by 4 publications

References 29 publications

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

Phenotypic variability in LAMA3‐associated amelogenesis imperfecta

Importance of Metalloproteinase 8 (MMP-8) in the Diagnosis of Periodontitis

Contact Info

Product

Resources

About