GPR68 and Hypomaturation Amelogenesis Imperfecta

Autosomal recessive hypomaturation amelogenesis imperfecta (AI) is characterized by poorly mineralized enamel with brownish-yellow discoloration and increased fragility. Two unrelated probands have been reported with biallelic GPR68 variants: a novel homozygous missense variant c.149T>A (p.Ile50Asn) in a Chinese family (one proband) and a homozygous frameshift c.78_83delinsC (p.Val27CysfsTer146) in a consanguineous family (one proband) ([PMID:38761453]; [PMID:35055328]). Both variants segregate with hypomaturation AI under an autosomal recessive model, and enamel from the missense proband showed disrupted prismatic structure and altered Ca/P ratios by SEM and EDX.

Functional assays of a familial AI missense mutant p.Leu74Pro demonstrate severely impaired proton-sensing, intracellular Ca2+ mobilization, and receptor internalization in HEK293 cells, consistent with a loss-of-function mechanism ([PMID:32279993]). These data support that pathogenic GPR68 variants disrupt enamel maturation via impairment of pH-sensing signaling.

Key take-home: Biallelic loss-of-function variants in GPR68 should be considered in the diagnostic evaluation of hypomaturation amelogenesis imperfecta.

References

• Archives of oral biology • 2024 • A novel mutation in GPR68 causes hypomaturation amelogenesis imperfecta. PMID:38761453
• Journal of personalized medicine • 2021 • Novel Mutations in GPR68 and SLC24A4 Cause Hypomaturation Amelogenesis Imperfecta. PMID:35055328
• Biochemical and biophysical research communications • 2020 • A missense mutation of Leu74Pro of OGR1 found in familial amelogenesis imperfecta actually causes the loss of the pH-sensing mechanism. PMID:32279993

Evidence Based Scoring (AI generated)