A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities

Smith, Claire E. L.; Kirkham, Jennifer; Day, Peter; Soldani, Francesca; McDerra, Esther J.; Poulter, James A.; Inglehearn, C. F.; Mighell, Alan J.; Brookes, Steven J.

doi:10.3389/fphys.2017.00333

Cited by 16 publications

(24 citation statements)

References 31 publications

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“…Delayed removal of enamel proteins may cause hypomaturation AI due to defective enamel biomineralization 17 . Genetic studies in human and mice confirm that KLK4 is critical for proper maturation of enamel crystals 18 , 19 . Collectively, the process of enamel development requires tight control of both spatial and temporal expressions of numerous genes.…”

Section: Introductionmentioning

confidence: 93%

Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development

Chu

Yan

Xian

et al. 2018

Sci Rep

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Runt-related transcription factor 2 (Runx2) is involved in the early stage of tooth development. However, only few studies have reported the role of Runx2 in enamel development, which may be attributed to that Runx2 full knockout mice cannot survive after birth. In the present study, we successfully established a Runx2-deficient mouse model using a conditional knockout (cKO) method. We observed a significant reduction in the degree of mineralization and the decreased size of enamel rods in cKO mice. Histological analysis showed the retained enamel proteins in enamel layer at maturation stage in cKO molars. Further analysis by qRT-PCR revealed that the expressions of genes encoding enamel structure proteins, such as amelogenin (AMELX), ameloblastin (AMBN) and enamelin (ENAM), were increased in cKO enamel organs. On the other hand, the expression of kallikrein-related peptidase-4 (KLK4) at the mRNA and protein levels was dramatically decreased from late secretory stage to maturation stage in cKO enamel organs, while the expression of matrix metalloproteinase-20 (MMP-20) was not significantly altered. Finally, immunohistochemistry indicated that the uptake of amelogenins by ameloblasts was significantly decreased in cKO mice. Taken together, Runx2 played critical roles in controlling enamel maturation by increasing synthesis of KLK4 and decreasing synthesis of AMELX, AMBN and ENAM.

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Section: Introductionmentioning

confidence: 93%

Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development

Chu

Yan

Xian

et al. 2018

Sci Rep

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“…All four KLK4 variants reported so far are either nonsense or frameshift mutations (Hart et al, 2004; Wright et al, 2011; Wang et al, 2013b; Smith et al, 2017a). However, only two of the four are predicted to lead to NMD.…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

“…Prior to the identification of the frameshift variant, c.632delT only three KLK4 variants in four families had been identified. However, the c.632delT variant, reported to occur at a frequency of 0.15% in the South Asian population, has been reported in five Pakistani families with hypomaturation AI and is predicted to disrupt three of six structurally important disulphide bonds (Smith et al, 2017a). Characterization of the human enamel phenotype revealed that overall the enamel was hypomineralized but that the deeper (inner) enamel was more seriously affected than the more superficial (outer) enamel (Smith et al, 2017a).…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

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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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“…Read processing and variant calling were performed using in-house developed pipelines. 13–17 Copy-number analysis was performed using the R package ExomeDepth. 18 Variants were confirmed and segregated by Sanger sequencing using the BigDye Terminator v3.1 kit (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

Sompele

Smith

Karali

et al. 2019

Genetics in Medicine

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PurposeRAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.MethodsExome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.ResultsBiallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.ConclusionThis study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.

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A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities

Cited by 16 publications

References 31 publications

Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development

Ablation of Runx2 in Ameloblasts Suppresses Enamel Maturation in Tooth Development

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease

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