A novel de novo mutation in <i><scp>LAMB</scp>3</i> causes localized hypoplastic enamel in the molar region

Kim, Young-Jae; Shin, Teo Jeon; Hyun, Hong‐Keun; Lee, Sanghoon; Lee, Zang H.; Kim, Jung-Wook

doi:10.1111/eos.12280

Cited by 15 publications

(16 citation statements)

References 19 publications

(27 reference statements)

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“…To date, 18 other genes have been shown causing non-syndromic AI: AMELX (16 different mutations; Kim et al, 2017), FAM83H (14, Pourhashemi et al, 2014), WDR72 (10, Hentschel et al, 2016), ENAM (4; Pavlic et al, 2007; Seymen et al, 2014), ITGB6/4 (4; Poulter et al, 2014; Wang et al, 2014b), SLC24A4 (3; Wang et al, 2014b), LAMA3 (3, Gostyńska et al, 2016), GPR68 (3, Parry et al, 2016b), LTBP3 (3; Huckert et al, 2015), AMBN (2; Prasad et al, 2016a), KLK4 (2; Lu et al, 2008; Wang et al, 2013), DLX3 (2; Kim et al, 2016b), STIM1 (2; Wang et al, 2014b; Parry et al, 2016a), COL17A1 (1; Prasad et al, 2016b), C4orf26 (1; Prasad et al, 2016b), LAMB3 (1; Kim et al, 2016c), ACPT (1, Seymen et al, 2016), and AMTN (1, Smith et al, 2016). A total of 13 different mutations on the gene sequence causing AI places MMP20 among the top three sensitive proteins involved in non-syndromic AI when mutated.…”

Section: Resultsmentioning

confidence: 99%

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

et al. 2017

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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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Section: Resultsmentioning

confidence: 99%

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

et al. 2017

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“…Carriers of the JEB-causing LAMA3 frameshift mutation c.488delG were found to have rough, pitted enamel due to haploinsufficiency of the protein (Yuen et al, 2012). One report of a patient carrying a LAMB3 mutation highlighted that the multi-cusped teeth were more severely affected by AI than the anterior teeth (Kim et al, 2016b), although further study is required to determine whether this is a general trend.…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene AMELX, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and in vitro studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the possibility of novel treatments and prevention strategies for AI.

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“…This would be particularly important in patients without a family history of AI, who are not already receiving additional monitoring. Indeed, dominant, de novo variants have been reported in AI . Increased genetic testing would also benefit children known to be at risk for AI, as testing completed before primary tooth eruption would allow for the treatment plan to be designed before primary tooth eruption.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, dominant, de novo variants have been reported in AI. 20,21 Increased genetic testing would also benefit children known to be at risk for AI, as testing completed before primary tooth eruption would allow for the treatment plan to be designed before primary tooth eruption. Another important consideration in the overall management of patients with AI is the psychosocial impact.…”

Section: Discussionmentioning

confidence: 99%

Examination of rare genetic variants in dental enamel genes: The potential role of next‐generation sequencing in primary dental care

Farrow

Venugopalan

Thiffault

et al. 2019

Orthod Craniofacial Res

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Structured Abstract Objectives To examine the potential role of next‐generation sequencing (NGS) and genetic testing to guide preventive care in dental enamel disorders using publicly available databases to access the frequency of deleterious alleles in AMTN, AMLEX and ENAM, associated with amelogenesis imperfecta (AI). Setting and Sample Population Public resources, including gnomAD (The Broad Institute) and the Center for Pediatric Genomic Medicine's warehouse, which together contain variants from nearly 145 000 exomes and genomes. Material & Methods Public resources, including sequencing data from ~145 000 exomes and genomes were queried for predicted loss of function variants with a minor allele frequency <1% in AMTN, AMLEX and ENAM. Results A total of 95 variants were identified in the combined dataset. If confirmed, this could be diagnostic for autosomal dominant AI. Conclusions The rapid integration of NGS into clinical care allows for the expansion of genetic testing for disorders that are not currently tested routinely, including non‐syndromic dental enamel disorders. A genotypic‐driven diagnosis of a disorder of enamel development could impact dental care, especially in young children, including early and more frequent monitoring to prevent complications. As new gene‐disease associations continue to emerge, including those for common and non‐syndromic craniofacial disorders, the possibility of genomic‐guided precision medicine and dentistry and the development of targeted, individualized therapeutics into standard clinical care will increase substantially.

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A novel de novo mutation in LAMB3 causes localized hypoplastic enamel in the molar region

Cited by 15 publications

References 19 publications

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Examination of rare genetic variants in dental enamel genes: The potential role of next‐generation sequencing in primary dental care

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