Mature enamel is a thin outer protective layer and covers the crown of the tooth in the form of a shell . Naturally, it is tough, hard, and highly mineralized translucent human tissue produced by ameloblasts and is epithelial in its origin . The biochemical architecture of dental enamel is of crystals of substituted calcium hydroxyapatite (96%), and the 4% is of organic matter and water . Amelogenesis is a highly intricate biomineralizing process controlled by the expression of several genes . AI affects both the primary and permanent dentition with exceptionally variable severity of the disease conditions [4, 5].
Various accounts of both syndromic and non-syndromic/isolated cases of AI have been published in the literature. Depending upon the amount, structure, and composition of the dental enamel, the phenotypes of non-syndromic AI are highly variable and may be divided into hypoplastic, hypocalcified, and hypomaturation forms [3, 4].
To date, pathogenic variants causing non-syndromic AI have been identified in 20 genes at various chromosomal locations , including AMELX (OMIM 300391; Xp22.2), a candidate gene for X-linked dominant hypoplastic AI (OMIM: 301200) , encoding an enamel matrix protein (EMPs) called amelogenin and making up to 90% of the ameloblast secreted EMPs [7, 8]. ENAM (OMIM 606585; 4q13.3), encoding the largest EMP called enamelin, a tooth specific protein expressed by ameloblasts, causing an autosomal recessive (OMIM: 204650) and dominant forms of AI (OMIM 104500) [9, 10]. AMBN (OMIM 601259; 4q13.3) encodes a glycine, leucine, and proline-rich enamel matrix protein called ameloblastin, a second most abundant protein expressed during amelogenesis. AMBN associated AI segregates in an autosomal recessive fashion [11, 12]. LAMB3 (OMIM 150310; 1q32.2), LAMA3 (OMIM 600805; 18q11.2), COL17A1 (OMIM 113811; 10q25.1), ITGB6 (OMIM 147558; 2q24.2) and ACPT (OMIM: 606362; 19q13.33) are other genes that cause hypoplastic AI in their altered forms [13,14,15,16,17,18,19,20]. Mutations in FAM83H (OMIM 611927; 8q24.3) cause an autosomal dominant hypocalcified type of AI [6, 21]. However, SLC24A4 (OMIM 609840; 14q32.12), WDR72 (OMIM 613214; 15q21.3), MMP20 (OMIM 604629; 11q22.2), KLK4 (OMIM 603767; 19q13.41) and GPR68 (OMIM 601404; 14q32.11), cause autosomal recessive hypomaturation type of AI [6, 22,23,24,25,26]. MMP20 (OMIM 604629; 11q22.2) and KLK4 (OMIM 603767; 19q13.41) are the two proteinases secreted at the time of enamel formation . Nevertheless, in the case of C4orf26 (OMIM 614829; 4q21.1), and AMTN (OMIM 610912; 4q13.3) mutations cause autosomal recessive and dominant hypo-mineralized amelogenesis imperfecta, respectively [28, 29]. Recently, RELT (OMIM 611211; 11q13.4) variants are identified, causing hypocalcified amelogenesis imperfecta type IIIC .
Occasionally, AI has been reported as a part of a syndrome. The most common of them include Tricho-Dento-Osseous (TDO; OMIM 190320) syndrome (DLX3, OMIM 600525), Laryngo-Onycho-Cutaneous (LOC; OMIM 245660) syndrome (LAMA3, OMIM 600805), Jalili syndrome (JS; OMIM 217080) (CNNM4, OMIM 607805), Amelogenesis Imperfecta and Nephrocalcinosis (OMIM 204690) (FAM20A, OMIM 611062), Kohlschutter-Tonz Syndrome (KTS; MIM 226750) (ROGDI, OMIM 614574), Amelo-Onycho-Hypohidrotic Syndrome (OMIM 104570), and Heimler Syndrome-1,2 (HMLR; OMIM 234580) (PEX1, PEX6, OMIM 602136, 601,498).
Here, we report a novel nonsense variant c.1192C > T (p.Gln398*) in exon-12 of SLC24A4 in non-syndromic AI patients in a family of Pakistani origin.