Title	Isolated Mutation of AMBN Affects Enamel Volume in Patients Susceptible to Hypoplastic Amelogenesis Imperfecta
Clinical Question	In patients susceptible to hypoplastic Amelogenesis Imperfecta (AI), does the isolated mutation of the ameloblastin gene, compared to the absence of variation, affect the enamel volume as a layer due to disrupted enamel formation?
Clinical Bottom Line	The isolated mutation of ameloblastin is recessively inherited and correlates with disrupted enamel formation, creating thin enamel volume as a layer. Patients susceptible to hypoplastic Amelogenesis Imperfecta have a notably thinner enamel volume and reduced mineral density in comparison to patients with the absence of variation in the ameloblastin gene.
Best Evidence
PubMed ID Author / Year Patient Group Study type (level of evidence) 24858907 Poulter 2014 Second cousin consanguineous family with three of the six children having hypoplastic AI Case Control Study Key results The study concerns a family of 8 in which three children have autosomal recessive hypoplastic amelogenesis imperfecta. The study mapped the family tree, in which unaffected parents were heterozygous carriers with perfectly normal teeth. Sanger sequencing and PCR revealed a 2,347-base-pair deletion (c.294 + 139_531 + 478del) that removed exon 6 from the AMBN gene. The deletion was in-frame; hence the protein structure was not completely destroyed; however, it shortened the protein by 79 amino acids (p.Tyr99_Glu177del). This results in the protein becoming unstable or functionally altered during enamel formation. The affected individuals within the study had severe hypoplastic amelogenesis imperfecta. Their teeth were thin, yellowish-brown, and had a rough enamel surface and reduced in mineral content; although the enamel remained relatively tough, the reduced enamel volume indicated that the enamel matrix was severely affected. 26502894 Prasad 2016 101 patients without molecular diagnosis with known and candidate genes in orodental disease Case Control Study Key results Of the 101 patients in the cohort that were screened, 50 unrelated patients had isolated AI, with 14 definitive diagnoses. Within the 14 diagnoses, only one subject had an autosomal recessive mutation in the AMBN gene. The parents of the subject were not affected, suggesting that the mutation is recessive. The mutation was a homozygous splice mutation at c.[532-1G>C]. The subject revealed hypoplastic clinical features, with “unrestored, yellow-tinged premolars and permanent molars.” The mutation is predicted to cause loss of function of Ambn through skipping of exon 7 or the retention of intron 6, leading to altered mRNA splicing and introduction of a premature stop codon. 31402633 Liang 2019 Three-generation Hispanic family with recessive AI Case Control Study Key results The study included a three-generation family with recessive AI, with one proband expressing AI. Enamel defects were correlated with the presence of compound heterozygous missense mutations in AMBN, p.Leu354Pro and p.Pro447Leu in exon 13. The mutations were both rare and autosomal recessive. The mother and half-sister of the proband were both heterozygous for p.Leu354Pro mutation, and “minor enamel pitting” was observed in both subjects. Intraoral photos of the proband at ages 10 and 12 reveal dental attrition and enamel hypoplasia in the primary dentition and secondary dentition, respectively. Panoramic radiographs do not detect radiodense enamel.
Evidence Search	PubMed: “amelogenesis imperfecta ameloblastin”, “genetic disorders with orodental involvement”
Comments on The Evidence	All three studies evaluated hypoplastic amelogenesis imperfecta in subjects and found mutations in the ameloblastin gene. The Poulter case-control study and laboratory study rigorously obtained findings using state-of-the-art techniques, such as PCR and Sanger sequencing, thereby confirming the 2,357 base-pair deletion in exon 6. The phenotypes characterized hypoplasticity in affected subjects. In addition, five deciduous teeth collected from family members were randomized and blindly analyzed. This study also noted that no photographs were taken of the deciduous teeth while they were in the children’s mouths. The Prasad case-control study tested the sensitivity of the gene panel through blind testing from the bioinformatician. The bioinformatician was unaware of the mutations and mode of inheritances in the clinical diagnoses. Ten out of ten mutations tested were detected by the gene panel. However, the authors acknowledge the low diagnostic rate of AI at 7%, which was likely due to the inclusion of patients without clear clinical diagnoses. Instead, whole exome sequencing would be a better-suited technology for determining the novel mutations. The Liang case-control study included ExAC and 1000 genomes database frequencies of the p.Leu354Pro mutation to establish the rarity. However, the ExAC and 1000 genome database frequency were not included for the p.Pro447Leu mutation. A heterozygous phenotype was not assessed for this mutation as well. Furthermore, whole exome sequencing was included to validate no potential further mutation-causing genes besides the 42 AI candidate genes. Techniques within the study were conducted based on established protocols.
Applicability	In clinical practice, patients with amelogenesis imperfecta may present hypoplastic phenotypic characteristics accompanied by dental sensitivity, esthetic, and masticatory dysfunctions. Reports reveal hypoplasticity of enamel in both primary and secondary teeth. Furthermore, a clinician can depict enamel volume and mineral content with radiographic methods as thin enamel volume and reduced grey values. It is imperative to note that the underlying complexity of the disease is unknown. Thus, it is important for clinicians to consider genetic counseling as a referral to rule out major medical complexities, such as distinguishing syndromic AI from isolated AI.
Specialty	(Pediatric Dentistry)
Keywords	Ameloblast, Ameloblastin, Amelogenesis Imperfecta, hypoplastic, enamel
ID#	3765
Date of submission	07/16/2026
E-mail	pheebeelii@gmail.com; dondraercarter@gmail.com
Author	Phoebe Li, Dondrae Carter
Co-author(s)
Co-author(s) e-mail
Faculty mentor	Yong-hee Patricia Chun, DDS, MS, PhD
Faculty mentor e-mail	chuny@uthscsa.edu
Basic Science Rationale (Mechanisms that may account for and/or explain the clinical question, i.e. is the answer to the clinical question consistent with basic biological, physical and/or behavioral science principles, laws and research?) None available
Comments and Evidence-Based Updates on the CAT (FOR PRACTICING DENTISTS', FACULTY, RESIDENTS and/or STUDENTS COMMENTS ON PUBLISHED CATs) None available