SLC24A4 – Hypomaturation Amelogenesis Imperfecta Type II

The SLC24A4 gene encodes a K⁺-dependent Na⁺/Ca²⁺ exchanger (NCKX4) critically expressed in ameloblasts during the maturation stage of enamel formation. Hypomaturation amelogenesis imperfecta Type II is an autosomal recessive disorder characterized by brownish-yellow discoloration, increased opacity, and poorly mineralized enamel prone to fracturing (HP:0006475; HP:0006484). Biallelic pathogenic variants in SLC24A4 disrupt calcium transport, leading to the AI phenotype.

Genetic studies first reported in 2013 identified a homozygous nonsense variant c.1015C>T (p.Arg339Ter) and a missense variant c.1495A>T (p.Ser499Cys) in two unrelated families with hypomineralized AI (PMID:23375655). These variants segregated with disease and were predicted to abolish exchanger function. Subsequent screening confirmed additional families and variant types.

In 2021, whole‐exome sequencing of three hypomaturation AI families uncovered two more homozygous SLC24A4 variants: c.613C>T (p.Arg205Ter) in Family 2 and c.437C>T (p.Ala146Val) in Family 3, each co‐segregating with autosomal recessive AI (PMID:35055328). These findings expanded the spectrum to four distinct families.

A 2020 consanguineous Pakistani pedigree demonstrated a novel nonsense c.1192C>T (p.Gln398Ter) segregating with AI in all affected individuals (PMID:32380970). In the same year, a Syrian family revealed that homozygous c.1604G>A (p.Gly535Asp) causes severe hypomaturation defects, while heterozygous carriers exhibit mild enamel hypomaturation, suggesting a dosage effect (PMID:32034543).

Functional assays in HEK293 cells showed that AI‐associated NCKX4 variants have absent or markedly reduced Ca²⁺ exchange activity, confirming loss‐of‐function as the disease mechanism (PMID:27129268; PMID:23375655). Furthermore, Slc24a4-null mice recapitulate enamel hypomaturation, linking genotype to phenotype in vivo (PMID:23375655).

No conflicting evidence has been reported. Collectively, six unrelated families, robust AR segregation, and concordant in vitro and in vivo functional data over >8 years establish a definitive gene‐disease relationship.

Key Take-home: SLC24A4 genetic testing is clinically actionable for diagnosing autosomal recessive hypomaturation AI Type II, informing patient management and genetic counseling.

References

• American Journal of Human Genetics • 2013 • Identification of mutations in SLC24A4, encoding a potassium-dependent sodium/calcium exchanger, as a cause of amelogenesis imperfecta. PMID:23375655
• Journal of personalized medicine • 2021 • Novel Mutations in GPR68 and SLC24A4 Cause Hypomaturation Amelogenesis Imperfecta. PMID:35055328
• BMC Medical Genetics • 2020 • A novel nonsense variant in SLC24A4 causing a rare form of amelogenesis imperfecta in a Pakistani family. PMID:32380970
• Clinical Oral Investigations • 2020 • Expanding the phenotype of hypomaturation amelogenesis imperfecta due to a novel SLC24A4 variant. PMID:32034543
• The Journal of Biological Chemistry • 2016 • A Functional Study of Mutations in K+-dependent Na+-Ca2+ Exchangers Associated with Amelogenesis Imperfecta and Non-syndromic Oculocutaneous Albinism. PMID:27129268

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