Novel KLK4 Mutations Cause Hypomaturation Amelogenesis Imperfecta

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Lee Y., Zhang H., Seymen F., Kim Y. J., Kasimoglu Y., Koruyucu M., ...More

JOURNAL OF PERSONALIZED MEDICINE, vol.12, no.2, 2022 (SCI-Expanded, Scopus) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 12 Issue: 2
  • Publication Date: 2022
  • Doi Number: 10.3390/jpm12020150
  • Journal Name: JOURNAL OF PERSONALIZED MEDICINE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, EMBASE, Directory of Open Access Journals
  • Keywords: whole exome sequencing, kallikrein 4, amelogenesis imperfecta, genetic diseases, hypomaturation, zymography, HUMAN TISSUE KALLIKREIN, ENAMEL DEFECTS, PEPTIDASE 4, MMP20, FAMILY, ACTIVATION, EXPRESSION, MATURATION, PHENOTYPES, DECAY
  • Open Archive Collection: AVESIS Open Access Collection
  • Istanbul University Affiliated: Yes

Abstract

Amelogenesis imperfecta (AI) is a group of rare genetic diseases affecting the tooth enamel. AI is characterized by an inadequate quantity and/or quality of tooth enamel and can be divided into three major categories: hypoplastic, hypocalcified and hypomaturation types. Even though there are some overlapping phenotypes, hypomaturation AI enamel typically has a yellow to brown discoloration with a dull appearance but a normal thickness indicating a less mineralized enamel matrix. In this study, we recruited four Turkish families with hypomaturation AI and performed mutational analysis using whole exome sequencing. These analyses revealed two novel homozygous mutations in the KLK4 gene: a nonsense mutation in exon 3 (NM_004917.4:c.170C>A, p.(Ser57*)) was found in families 1, 2 and 3 and a missense mutation in exon 6 (c.637T>C, p.(Cys213Arg)) in family 4. Functional analysis showed that the missense mutation transcript could not translate the mutant protein efficiently or generated an unstable protein that lacked functional activity. The two novel inactivating KLK4 mutations we identified caused a hypomaturation AI phenotype similar to those caused by the four previously described KLK4 nonsense and frameshift mutations. This study improves our understanding of the normal and pathologic mechanisms of enamel formation.