Versões
- 2024-07-12 (2)
- 2021-09-30 (1)
Palavras-chave
amelogênese imperfeita
hipoplasia
esmalte
hipoplasia
esmalte
Como Citar
Mecanismos moleculares da amelogênese imperfeita. Uma revisão dos genes ENAM, AMBN, FAM83H, MMP20 e KLK4. (2021). Odontoestomatología, 23(38). https://doi.org/10.22592/1688-9339-ode-23-38-e306
Resumo
A amelogênese imperfeita (AI) é uma doença hereditária que afeta a estrutura e aparência clínica do esmalte dentário. Mutações de 18 genes têm sido associadas como causa do AI. O objetivo deste trabalho é atualizar o conhecimento atual sobre genes ENAM, AMBN, FAM83H, MMP20 e KLK4 que causam os diferentes tipos de IA.
Metodologia: Foi realizada uma busca bibliográfica considerando artigos científicos de 2003 até 2021 sobre mutações específicas nos genes citados nos seguintes portais:
scielo, Pubmed / MEDLINE, Cochrane e Springer Link.
Resultados: 37 artigos atenderam aos critérios de inclusão e foram utilizados para o desenvolvimento desta revisão.
Conclusões: Dependendo do gene envolvido, as alterações do esmalte podem apresentar uma variedade de características. Os mecanismos biológicos que levam à doença são múltiplos e variados, porém muitos de les ainda não estão totalmente esclarecidos, portanto, mais pesquisas serão necessárias para melhorar nossa compreensão do assunto.
Referências
1. Sapp J.P; Eversole L.R; Wysocki G.P. Patología oral y maxilofacial contemporánea, 2º edición. Madrid: Elsevier, 2005: 14-16.
2. Witkop C.J. Jr. Amelogenesis imperfecta, dentinogenesisimperfecta and dentin dysplasia revisited: problems in classification. J. Oral. Pathol. 1988; 17(9-10): 547-553.
3. Crawford P.J; Aldred M; Bloch-Zupan A. Amelogenesis imperfecta. Orphanet J. Rare. Dis. 2007; 2: 17.
4. Hu J.C; Chun Y.H; Al Hazzazzi T; Simmer J.P. Enamel formation and amelogenesis imperfecta. Cellstissuesorgans. 2007; 186(1): 78-85.
5. Aldred M.J; Crawford P.J.M; Savarirayan R. Amelogenesis imperfecta: a classification and catalogue for the 21st century. Oral. Dis. 2003; 9(1): 19-23.
6. Prasad M.K; Laouina S; El Alloussi M; Dollfus H; Bloch-Zupan A. Amelogenesis imperfecta: 1 family, 2 phenotypes, and 2 mutated genes. J. Dent. Res. 2016; 95(13): 1457-1463.
7. Smith C.E.L; Poulter J.A; Antanaviciute A; Kirkham J; Brookes S.J; Inglehearn C.F; Mighell A.J. Amelogenesis Imperfecta; Genes, Proteins, and Pathways. Front. Physiol. 2017; 8: 435.
8. Kim J.W; Simmer J.P; Lin B.P.L; Seymen F; Bartlett J.D; Hu J.C.C. Mutational analysis of candidate
genes in 24 amelogenesis imperfecta families. Eur. J. Oral. Sci. 2006; 114(suppl1): 3-12.
9. Simancas-Escorcia V; Natera A; Acosta de Camargo M.G. Genes involved in amelogenesis imperfecta. Part I. Rev. Fac. Odontol. Univ. Antioq. 2018; 30(1): 105-120.
10. Lee S.K; Lee K.E; Jeong T.S; Hwang Y.H; Kim S; Hu J.C.C; Simmer J.P; Kim J.W. FAM83H mutations cause ADHCAI and alter intracellular protein localization. J. Dent. Res. 2011; 90(3): 377-381.
11. Kim J.W; Lee S.K; Lee Z.H; Park J.C; Lee K.E; Lee M.H. FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am. J. Hum. Genet. 2008; 82(2): 489-494.
12. Zhang H; Hu Y; Seymen F; Koruyucu M; Kasimoglu Y; Wang S.K; Wright J.T; Havel M.W; Zhang C; Kim J.W; Simmer J.P; Hu J.C.C. ENAM mutations and Digenic Inheritance. Mol. Genet. Genomic Med. 2019; 7(10): e928.
13. Koruyucu M; Kang J; Kim Y.J; Seymen F; Kasimoglu Y; Lee Z.H; Shin T.J; Hyun H.K; Kim Y.J; Lee S.H; Hu J.C.C; Simmer J.P; Kim J.W. Hypoplastic AI with highly variable expressivity caused by ENAM mutations. J. Dent. Res. 2018; 97(9): 1064-1069.
14. Seymen F; Lee K.E; Koruyucu M; Gencay K; Bayram M; Tuna E.B; Lee Z.H; Kim J.W. ENAM mutations with Incomplete Penetrance. J. Dent. Res. 2014; 93(10): 988-992.
15. Wang X; Zhao Y; Yang Y; Qin M. Novel ENAM and LAMB3 mutations in chinese families with hypoplastic amelogenesis imperfecta. Plos One. 2015; 10(3): e0116514.
16. Hart T.C; Hart P.S; Gorry M.C; Michalec M.D; Ryu O.H; Uygur C; Ozdemir D; Firatli S; Aren G; Firatli E. Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects. J. Med. Genet. 2003; 40(12): 900-906.
17. Siddiqui S; Al-Jawad M. Enamelin directs crystallite organization at the enamel-dentine junction. J. Dent. Res. 2016; 95(5): 580-587.
18. Brookes S.J; Barron M.J; Smith C.E.L; Poulter J.A; Mighell A.J; Inglehearn C.F; Brown C.J; Rodd H; Kirkham J; Dixon M.J. Amelogenesis imperfecta caused by N-Terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress. Hum. Mol. Genet. 2017; 26(10): 1863-1876.
19. Delsuc F; Gasse B; Sire J.Y. Evolutionary analysis of selective constraints identifies ameloblastin (AMBN) as a potential candidate for amelogenesis imperfecta. BMC Evolutionary Biology. 2015; 15: 148.
20. Poulter J.A; Murillo G; Brookes S.J; Smith C.E.L; Parry D.A; Silva S; Kirkham J; Inglehearn C.F; Mighell A.J. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta. Hum. Mol. Genet. 2014; 23(20): 5317-5324.
21. Fukumoto S; Kiba T; Hall B; Iehara N; Nakamura T; Longenecker G; Krebsbach P.H; Nanci A; Kulkarni A.B; Yamada Y. Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts. J. Cell Biol. 2004; 167(5): 973-983.
22. Sire J.Y; Davit-Béal T; Delgado S; Gu X. The origin and evolution of enamel mineralization genes. Cells Tissues Organs. 2007; 186(1): 25-48.
23. Liang T; Hu Y; Smith C.E; Richardson A.S; Zhang H; Yang J; Lin B; Wang S.K; Kim J.W; Chun Y.H; Simmer J.P; Hu J.C.C. AMBN mutations causing hypoplastic amelogenesis imperfecta and Ambn knockout-NLS-laczknockin mice exhibiting failed amelogenesis and Ambn tissue-specificity. Mol. Genet. Genomic Med. 2019; 7(9): e929.
24. Lu T; Li M; Xu X; Xiong J; Huang C; Zhang X; Hu A; Peng L; Cai D; Zhang L; Wu B; Xiong F. Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders. Int. J. Oral Sci. 2018; 10(3): 26.
25. Wang S.K; Zhang H; Hu C.Y; Liu J.F; Chadha S; Kim J.W; Simmer J.P; Hu J.C.C. FAM83H and autosomal dominant hypocalcified amelogenesis imperfecta. J. Dent. Res. 2021; 100(3): 293-301.
26. Urzua B; Martinez C; Ortega-Pinto A; Adorno D; Morales-Bozo I; Riadi G; Jara L; Plaza A; Lefimil C; Lozano C; Reyes M. Novel missense mutation of the FAM83H gene causes retention of amelogenin and a mild clinical phenotype of hypocalcified enamel. Arch. Oral Biol. 2015; 60(9): 1356-1367.
27. Wang S.K; Hu Y; Yang J; Smith C.E; Richardson A.S; Yamakoshi Y; Lee Y.L; Seymen F; Koruyucu M; Gencay K; Lee M; Choi M; Kim J.W; Hu J.C.C; Simmer J.P. Fam83h null mice support a neomorphic mechanism for human ADHCAI. Mol. Genet. Genomic Med. 2015; 4(1): 46-67.
28. Wang S.K; Hu Y; Smith C.E; Yang J; Zeng C; Kim J.W; Hu J.C.C; Simmer J.P. The enamel phenotype in homozygous Fam83h truncation mice. Mol. Genet. Genomic Med. 2019; 7(6): e724.
29. Zheng, Y; Lu T; Chen J; Li M; Xiong J; He F; Gan Z; Guo Y; Zhang L; Xiong F. The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a chinese family. Clin. Oral Invest. 2021; 25(5): 2915-2923.
30. Xin W; Wenjun W; Man Q; Yuming Z. Novel FAM83H mutations in patients with amelogenesis imperfecta. Sci. Rep. 2017; 7(1): 6075.
31. Yu S; Quan J; Wang X; Sun X; Zhang X; Liu Y; Zhang C; Zheng S. A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta. Mutagenesis. 2018; 33(4): 333-340.
32. Zhang C; Song Y; Bian Z; Ultrastructural analysis of the teeth affected with amelogenesis imperfecta resulting from FAM83H mutations and review of the literatures. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015; 119(2): e69-76.
33. Kuga T; Sasaki M; Mikami T; Miake Y; Adachi J; Shimizu M; Saito Y; Koura M; Takeda Y; Matsuda J; Tomonaga T; Nakayama Y. FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes. Sci. Rep. 2016; 6: 26557.
34. Gasse B; Prasad M; Delgado S; Huckert M; Kawczynski M; Garret-Bernardin A; Lopez-Cazaux S; Bailleul-Forestier I; Manière M.C; Stoetzel C; Bloch-Zupan A; Sire J.Y. Evolutionary analysis predicts sensitive positions of MMP20 and validates newly-and previously-identified MMP20 mutations causing amelogenesis imperfecta. Front. Physiol. 2017; 8: 398.
35. Wang S.K; Zhang H; Chavez M.B; Hu Y; Seymen F; Koruyucu M; Kasimoglu Y; Colvin C.D; Kolli T.N; Tan M.H; Wang Y.L; Lu P.Y; Kim J.W; Foster B.L; Bartlett J.D; Simmer J.P; Hu J.C.C. Dental malformations associated with biallelic MMP20 mutations. Mol. Genet. Genomic Med. 2020; 8(8): e1307.
36. Seymen F; Park J.C; Lee K.E; Lee H.K; Lee D.S; Koruyucu M; Gencay K; Bayram M; Tuna E.B; Lee Z.H; Kim Y.J; Kim J.W. Novel MMP20 and KLK4 mutations in amelogenesis imperfecta. J. Dent. Res. 2015; 94(8): 1063-1069.
37. Kim Y.J; Kang J; Seymen F; Koruyucu M; Zhang H; Kasimoglu Y; Bayram M; Tuna-Ince E.B; Bayrak
S; Tuloglu N; Hu J.C.C; Simmer J.P; Kim J.W. Alteration of exon definition causes amelogenesis imperfecta. J. Dent. Res. 2020; 99(4): 410-418.
38. Kim Y.J; Kang J; Seymen F; Koruyucu M; Gencay K; Shin T.J; Hyun H.K; Lee Z.H; Hu J.C.C; Simmer J.P; Kim J.W. Analyses of MMP20 missense mutations in two families with hypomaturation amelogenesis imperfecta. Front. Physiol. 2017; 8: 229.
39. Hu Y; Smith C.E; Richardson A.S; Bartlett J.D; Hu J.C; Simmer J.P. MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation. Mol. Genet. Genomic Med. 2015; 4(2): 178-196.
40. Smith C.E.L; Kirkham J; Day P.F; Soldani F; mcderra E.J; Poulter J.A; Inglehearn C.F; Mighell A.J; Brookes S.J. A fourth KLK4 mutation is associated with enamel hypomineralisation and structural abnormalities. Front. Physiol. 2017; 8: 333.
41. Hart P.S; Hart T.C; Michalec M.D; Ryu, O.H; Simmons D; Hong S; Wright J.T. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J. Med. Genet. 2004; 41(7): 545-549.
42. Wang S.K; Hu Y; Simmer J.P; Seymen F; Estrella N.M.R.P; Pal S; Reid B.M; Yildirim M; Bayram M; Bartlett J.D; Hu J.C.C. Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing. J. Dent. Res. 2013; 92(3): 266-271.
2. Witkop C.J. Jr. Amelogenesis imperfecta, dentinogenesisimperfecta and dentin dysplasia revisited: problems in classification. J. Oral. Pathol. 1988; 17(9-10): 547-553.
3. Crawford P.J; Aldred M; Bloch-Zupan A. Amelogenesis imperfecta. Orphanet J. Rare. Dis. 2007; 2: 17.
4. Hu J.C; Chun Y.H; Al Hazzazzi T; Simmer J.P. Enamel formation and amelogenesis imperfecta. Cellstissuesorgans. 2007; 186(1): 78-85.
5. Aldred M.J; Crawford P.J.M; Savarirayan R. Amelogenesis imperfecta: a classification and catalogue for the 21st century. Oral. Dis. 2003; 9(1): 19-23.
6. Prasad M.K; Laouina S; El Alloussi M; Dollfus H; Bloch-Zupan A. Amelogenesis imperfecta: 1 family, 2 phenotypes, and 2 mutated genes. J. Dent. Res. 2016; 95(13): 1457-1463.
7. Smith C.E.L; Poulter J.A; Antanaviciute A; Kirkham J; Brookes S.J; Inglehearn C.F; Mighell A.J. Amelogenesis Imperfecta; Genes, Proteins, and Pathways. Front. Physiol. 2017; 8: 435.
8. Kim J.W; Simmer J.P; Lin B.P.L; Seymen F; Bartlett J.D; Hu J.C.C. Mutational analysis of candidate
genes in 24 amelogenesis imperfecta families. Eur. J. Oral. Sci. 2006; 114(suppl1): 3-12.
9. Simancas-Escorcia V; Natera A; Acosta de Camargo M.G. Genes involved in amelogenesis imperfecta. Part I. Rev. Fac. Odontol. Univ. Antioq. 2018; 30(1): 105-120.
10. Lee S.K; Lee K.E; Jeong T.S; Hwang Y.H; Kim S; Hu J.C.C; Simmer J.P; Kim J.W. FAM83H mutations cause ADHCAI and alter intracellular protein localization. J. Dent. Res. 2011; 90(3): 377-381.
11. Kim J.W; Lee S.K; Lee Z.H; Park J.C; Lee K.E; Lee M.H. FAM83H mutations in families with autosomal-dominant hypocalcified amelogenesis imperfecta. Am. J. Hum. Genet. 2008; 82(2): 489-494.
12. Zhang H; Hu Y; Seymen F; Koruyucu M; Kasimoglu Y; Wang S.K; Wright J.T; Havel M.W; Zhang C; Kim J.W; Simmer J.P; Hu J.C.C. ENAM mutations and Digenic Inheritance. Mol. Genet. Genomic Med. 2019; 7(10): e928.
13. Koruyucu M; Kang J; Kim Y.J; Seymen F; Kasimoglu Y; Lee Z.H; Shin T.J; Hyun H.K; Kim Y.J; Lee S.H; Hu J.C.C; Simmer J.P; Kim J.W. Hypoplastic AI with highly variable expressivity caused by ENAM mutations. J. Dent. Res. 2018; 97(9): 1064-1069.
14. Seymen F; Lee K.E; Koruyucu M; Gencay K; Bayram M; Tuna E.B; Lee Z.H; Kim J.W. ENAM mutations with Incomplete Penetrance. J. Dent. Res. 2014; 93(10): 988-992.
15. Wang X; Zhao Y; Yang Y; Qin M. Novel ENAM and LAMB3 mutations in chinese families with hypoplastic amelogenesis imperfecta. Plos One. 2015; 10(3): e0116514.
16. Hart T.C; Hart P.S; Gorry M.C; Michalec M.D; Ryu O.H; Uygur C; Ozdemir D; Firatli S; Aren G; Firatli E. Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects. J. Med. Genet. 2003; 40(12): 900-906.
17. Siddiqui S; Al-Jawad M. Enamelin directs crystallite organization at the enamel-dentine junction. J. Dent. Res. 2016; 95(5): 580-587.
18. Brookes S.J; Barron M.J; Smith C.E.L; Poulter J.A; Mighell A.J; Inglehearn C.F; Brown C.J; Rodd H; Kirkham J; Dixon M.J. Amelogenesis imperfecta caused by N-Terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress. Hum. Mol. Genet. 2017; 26(10): 1863-1876.
19. Delsuc F; Gasse B; Sire J.Y. Evolutionary analysis of selective constraints identifies ameloblastin (AMBN) as a potential candidate for amelogenesis imperfecta. BMC Evolutionary Biology. 2015; 15: 148.
20. Poulter J.A; Murillo G; Brookes S.J; Smith C.E.L; Parry D.A; Silva S; Kirkham J; Inglehearn C.F; Mighell A.J. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta. Hum. Mol. Genet. 2014; 23(20): 5317-5324.
21. Fukumoto S; Kiba T; Hall B; Iehara N; Nakamura T; Longenecker G; Krebsbach P.H; Nanci A; Kulkarni A.B; Yamada Y. Ameloblastin is a cell adhesion molecule required for maintaining the differentiation state of ameloblasts. J. Cell Biol. 2004; 167(5): 973-983.
22. Sire J.Y; Davit-Béal T; Delgado S; Gu X. The origin and evolution of enamel mineralization genes. Cells Tissues Organs. 2007; 186(1): 25-48.
23. Liang T; Hu Y; Smith C.E; Richardson A.S; Zhang H; Yang J; Lin B; Wang S.K; Kim J.W; Chun Y.H; Simmer J.P; Hu J.C.C. AMBN mutations causing hypoplastic amelogenesis imperfecta and Ambn knockout-NLS-laczknockin mice exhibiting failed amelogenesis and Ambn tissue-specificity. Mol. Genet. Genomic Med. 2019; 7(9): e929.
24. Lu T; Li M; Xu X; Xiong J; Huang C; Zhang X; Hu A; Peng L; Cai D; Zhang L; Wu B; Xiong F. Whole exome sequencing identifies an AMBN missense mutation causing severe autosomal-dominant amelogenesis imperfecta and dentin disorders. Int. J. Oral Sci. 2018; 10(3): 26.
25. Wang S.K; Zhang H; Hu C.Y; Liu J.F; Chadha S; Kim J.W; Simmer J.P; Hu J.C.C. FAM83H and autosomal dominant hypocalcified amelogenesis imperfecta. J. Dent. Res. 2021; 100(3): 293-301.
26. Urzua B; Martinez C; Ortega-Pinto A; Adorno D; Morales-Bozo I; Riadi G; Jara L; Plaza A; Lefimil C; Lozano C; Reyes M. Novel missense mutation of the FAM83H gene causes retention of amelogenin and a mild clinical phenotype of hypocalcified enamel. Arch. Oral Biol. 2015; 60(9): 1356-1367.
27. Wang S.K; Hu Y; Yang J; Smith C.E; Richardson A.S; Yamakoshi Y; Lee Y.L; Seymen F; Koruyucu M; Gencay K; Lee M; Choi M; Kim J.W; Hu J.C.C; Simmer J.P. Fam83h null mice support a neomorphic mechanism for human ADHCAI. Mol. Genet. Genomic Med. 2015; 4(1): 46-67.
28. Wang S.K; Hu Y; Smith C.E; Yang J; Zeng C; Kim J.W; Hu J.C.C; Simmer J.P. The enamel phenotype in homozygous Fam83h truncation mice. Mol. Genet. Genomic Med. 2019; 7(6): e724.
29. Zheng, Y; Lu T; Chen J; Li M; Xiong J; He F; Gan Z; Guo Y; Zhang L; Xiong F. The gain-of-function FAM83H mutation caused hypocalcification amelogenesis imperfecta in a chinese family. Clin. Oral Invest. 2021; 25(5): 2915-2923.
30. Xin W; Wenjun W; Man Q; Yuming Z. Novel FAM83H mutations in patients with amelogenesis imperfecta. Sci. Rep. 2017; 7(1): 6075.
31. Yu S; Quan J; Wang X; Sun X; Zhang X; Liu Y; Zhang C; Zheng S. A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta. Mutagenesis. 2018; 33(4): 333-340.
32. Zhang C; Song Y; Bian Z; Ultrastructural analysis of the teeth affected with amelogenesis imperfecta resulting from FAM83H mutations and review of the literatures. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2015; 119(2): e69-76.
33. Kuga T; Sasaki M; Mikami T; Miake Y; Adachi J; Shimizu M; Saito Y; Koura M; Takeda Y; Matsuda J; Tomonaga T; Nakayama Y. FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes. Sci. Rep. 2016; 6: 26557.
34. Gasse B; Prasad M; Delgado S; Huckert M; Kawczynski M; Garret-Bernardin A; Lopez-Cazaux S; Bailleul-Forestier I; Manière M.C; Stoetzel C; Bloch-Zupan A; Sire J.Y. Evolutionary analysis predicts sensitive positions of MMP20 and validates newly-and previously-identified MMP20 mutations causing amelogenesis imperfecta. Front. Physiol. 2017; 8: 398.
35. Wang S.K; Zhang H; Chavez M.B; Hu Y; Seymen F; Koruyucu M; Kasimoglu Y; Colvin C.D; Kolli T.N; Tan M.H; Wang Y.L; Lu P.Y; Kim J.W; Foster B.L; Bartlett J.D; Simmer J.P; Hu J.C.C. Dental malformations associated with biallelic MMP20 mutations. Mol. Genet. Genomic Med. 2020; 8(8): e1307.
36. Seymen F; Park J.C; Lee K.E; Lee H.K; Lee D.S; Koruyucu M; Gencay K; Bayram M; Tuna E.B; Lee Z.H; Kim Y.J; Kim J.W. Novel MMP20 and KLK4 mutations in amelogenesis imperfecta. J. Dent. Res. 2015; 94(8): 1063-1069.
37. Kim Y.J; Kang J; Seymen F; Koruyucu M; Zhang H; Kasimoglu Y; Bayram M; Tuna-Ince E.B; Bayrak
S; Tuloglu N; Hu J.C.C; Simmer J.P; Kim J.W. Alteration of exon definition causes amelogenesis imperfecta. J. Dent. Res. 2020; 99(4): 410-418.
38. Kim Y.J; Kang J; Seymen F; Koruyucu M; Gencay K; Shin T.J; Hyun H.K; Lee Z.H; Hu J.C.C; Simmer J.P; Kim J.W. Analyses of MMP20 missense mutations in two families with hypomaturation amelogenesis imperfecta. Front. Physiol. 2017; 8: 229.
39. Hu Y; Smith C.E; Richardson A.S; Bartlett J.D; Hu J.C; Simmer J.P. MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation. Mol. Genet. Genomic Med. 2015; 4(2): 178-196.
40. Smith C.E.L; Kirkham J; Day P.F; Soldani F; mcderra E.J; Poulter J.A; Inglehearn C.F; Mighell A.J; Brookes S.J. A fourth KLK4 mutation is associated with enamel hypomineralisation and structural abnormalities. Front. Physiol. 2017; 8: 333.
41. Hart P.S; Hart T.C; Michalec M.D; Ryu, O.H; Simmons D; Hong S; Wright J.T. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J. Med. Genet. 2004; 41(7): 545-549.
42. Wang S.K; Hu Y; Simmer J.P; Seymen F; Estrella N.M.R.P; Pal S; Reid B.M; Yildirim M; Bayram M; Bartlett J.D; Hu J.C.C. Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing. J. Dent. Res. 2013; 92(3): 266-271.