Novel Mutations in GPR68 and SLC24A4 Cause Hypomaturation Amelogenesis Imperfecta.

Figen Seymen,James P Simmer,Hong Zhang,Mine Koruyucu,Jan C.-C Hu,Jung-Wook Kim,Yelda Kasimoglu

doi:10.3390/jpm12010013

Abstract

Amelogenesis imperfecta (AI) is a rare genetic condition affecting the quantity and/or quality of tooth enamel. Hypomaturation AI is characterized by brownish-yellow discoloration with increased opacity and poorly mineralized enamel prone to fracture and attrition. We recruited three families affected by hypomaturation AI and performed whole exome sequencing with selected individuals in each family. Bioinformatic analysis and Sanger sequencing identified and confirmed mutations and segregation in the families. Family 1 had a novel homozygous frameshift mutation in GPR68 gene (NM_003485.3:c.78_83delinsC, p.(Val27Cysfs*146)). Family 2 had a novel homozygous nonsense mutation in SLC24A4 gene (NM_153646.4:c.613C>T, NP_705932.2:p.(Arg205*)). Family 3 also had a homozygous missense mutation in SLC24A4 gene which was reported previously (c.437C>T, p.(Ala146Val)). This report not only expands the mutational spectrum of the AI-causing genes but also improves our understanding of normal and pathologic amelogenesis.

Highlights

Tooth enamel is the hardest tissue in the human body, covering the crown of the tooth to protect the underlying dentin–pulp complex and to enhance esthetics and facilitate masticatory function
The coordinated pH sensing and ion transportation of ameloblasts are critical for optimal enamel maturation [3,4]
The analyses revealed a novel frameshift mutation caused by an indel in the GPR68 gene and a novel nonsense mutation and a previously reported missense mutation in the SLC24A4 gene

Summary

Introduction

Tooth enamel is the hardest tissue in the human body, covering the crown of the tooth to protect the underlying dentin–pulp complex and to enhance esthetics and facilitate masticatory function. The formation of enamel begins with the ameloblasts’. When the ameloblasts enter the maturation stage, they cycle through the ruffle-ended and smoothended phases during which matrix proteins are further degraded and removed and rapid appositional growth of enamel is accelerated [2]. The coordinated pH sensing and ion transportation of ameloblasts are critical for optimal enamel maturation [3,4]. Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary defects affecting tooth enamel. Depending on how the hereditary defect impacts the specific stage of enamel formation, AI is classified into hypoplastic, hypocalcified, and hypomatured types [5]. AI-affected individuals suffer from poor esthetics and masticatory discomfort including hypersensitivity to cold and hot stimuli and marked impact on the psychosocial wellbeing, such as social avoidance, distress, and low self-esteem [6,7]

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