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A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities
“Amelogenesis imperfecta” (AI) describes a group of genetic conditions that result in defects in tooth enamel formation. Mutations in many genes are known to cause AI, including the gene encoding the serine protease, kallikrein related peptidase 4 (KLK4), expressed during the maturation stage of ame...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447068/ https://www.ncbi.nlm.nih.gov/pubmed/28611678 http://dx.doi.org/10.3389/fphys.2017.00333 |
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author | Smith, Claire E. L. Kirkham, Jennifer Day, Peter F. Soldani, Francesca McDerra, Esther J. Poulter, James A. Inglehearn, Christopher F. Mighell, Alan J. Brookes, Steven J. |
author_facet | Smith, Claire E. L. Kirkham, Jennifer Day, Peter F. Soldani, Francesca McDerra, Esther J. Poulter, James A. Inglehearn, Christopher F. Mighell, Alan J. Brookes, Steven J. |
author_sort | Smith, Claire E. L. |
collection | PubMed |
description | “Amelogenesis imperfecta” (AI) describes a group of genetic conditions that result in defects in tooth enamel formation. Mutations in many genes are known to cause AI, including the gene encoding the serine protease, kallikrein related peptidase 4 (KLK4), expressed during the maturation stage of amelogenesis. In this study we report the fourth KLK4 mutation to be identified in autosomal recessively-inherited hypomaturation type AI, c.632delT, p.(L211Rfs(*)37) (NM_004917.4, NP_004908.4). This homozygous variant was identified in five Pakistani AI families and is predicted to result in a transcript with a premature stop codon that escapes nonsense mediated decay. However, the protein may misfold, as three of six disulphide bonds would be disrupted, and may be degraded or non-functional as a result. Primary teeth were obtained from one affected individual. The enamel phenotype was characterized using high-resolution computerized X-ray tomography (CT), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and microhardness testing (MH). Enamel from the affected individual (referred to as KLK4 enamel) was hypomineralised in comparison with matched control enamel. Furthermore, KLK4 inner enamel was hypomineralised compared with KLK4 outer enamel. SEM showed a clear structural demarcation between KLK4 inner and outer enamel, although enamel structure was similar to control tissue overall. EDX showed that KLK4 inner enamel contained less calcium and phosphorus and more nitrogen than control inner enamel and KLK4 outer enamel. MH testing showed that KLK4 inner enamel was significantly softer than KLK4 outer enamel (p < 0.001). However, the hardness of control inner enamel was not significantly different to that of control outer enamel. Overall, these findings suggest that the KLK4 c.632delT mutation may be a common cause of autosomal recessive AI in the Pakistani population. The phenotype data obtained mirror findings in the Klk4(−/−) mouse and suggest that KLK4 is required for the hardening and mineralization of the inner enamel layer but is less essential for hardening and mineralization of the outer enamel layer. |
format | Online Article Text |
id | pubmed-5447068 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54470682017-06-13 A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities Smith, Claire E. L. Kirkham, Jennifer Day, Peter F. Soldani, Francesca McDerra, Esther J. Poulter, James A. Inglehearn, Christopher F. Mighell, Alan J. Brookes, Steven J. Front Physiol Physiology “Amelogenesis imperfecta” (AI) describes a group of genetic conditions that result in defects in tooth enamel formation. Mutations in many genes are known to cause AI, including the gene encoding the serine protease, kallikrein related peptidase 4 (KLK4), expressed during the maturation stage of amelogenesis. In this study we report the fourth KLK4 mutation to be identified in autosomal recessively-inherited hypomaturation type AI, c.632delT, p.(L211Rfs(*)37) (NM_004917.4, NP_004908.4). This homozygous variant was identified in five Pakistani AI families and is predicted to result in a transcript with a premature stop codon that escapes nonsense mediated decay. However, the protein may misfold, as three of six disulphide bonds would be disrupted, and may be degraded or non-functional as a result. Primary teeth were obtained from one affected individual. The enamel phenotype was characterized using high-resolution computerized X-ray tomography (CT), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and microhardness testing (MH). Enamel from the affected individual (referred to as KLK4 enamel) was hypomineralised in comparison with matched control enamel. Furthermore, KLK4 inner enamel was hypomineralised compared with KLK4 outer enamel. SEM showed a clear structural demarcation between KLK4 inner and outer enamel, although enamel structure was similar to control tissue overall. EDX showed that KLK4 inner enamel contained less calcium and phosphorus and more nitrogen than control inner enamel and KLK4 outer enamel. MH testing showed that KLK4 inner enamel was significantly softer than KLK4 outer enamel (p < 0.001). However, the hardness of control inner enamel was not significantly different to that of control outer enamel. Overall, these findings suggest that the KLK4 c.632delT mutation may be a common cause of autosomal recessive AI in the Pakistani population. The phenotype data obtained mirror findings in the Klk4(−/−) mouse and suggest that KLK4 is required for the hardening and mineralization of the inner enamel layer but is less essential for hardening and mineralization of the outer enamel layer. Frontiers Media S.A. 2017-05-29 /pmc/articles/PMC5447068/ /pubmed/28611678 http://dx.doi.org/10.3389/fphys.2017.00333 Text en Copyright © 2017 Smith, Kirkham, Day, Soldani, McDerra, Poulter, Inglehearn, Mighell and Brookes. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Smith, Claire E. L. Kirkham, Jennifer Day, Peter F. Soldani, Francesca McDerra, Esther J. Poulter, James A. Inglehearn, Christopher F. Mighell, Alan J. Brookes, Steven J. A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title | A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title_full | A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title_fullStr | A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title_full_unstemmed | A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title_short | A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities |
title_sort | fourth klk4 mutation is associated with enamel hypomineralisation and structural abnormalities |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447068/ https://www.ncbi.nlm.nih.gov/pubmed/28611678 http://dx.doi.org/10.3389/fphys.2017.00333 |
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