Deletion of Slc26a1 and Slc26a7 Delays Enamel Mineralization in Mice

Abstract

Amelogenesis features two major developmental stages—secretory and maturation. During maturation stage, hydroxyapatite deposition and matrix turnover require delicate pH regulatory mechanisms mediated by multiple ion transporters. Several members of the Slc26 gene family (Slc26a1, Slc26a3, Slc26a4, Slc26a6, and Slc26a7), which exhibit bicarbonate transport activities, have been suggested by previous studies to be involved in maturation-stage amelogenesis, especially the key process of pH regulation. However, details regarding the functional role of these genes in enamel formation are yet to be clarified, as none of the separate mutant animal lines demonstrates any discernible enamel defects. Continuing with our previous investigation of Slc26a1−/− and Slc26a7−/− animal models, we generated a double-mutant animal line with the absence of both Slc26a1 and Slc26a7. We showed in the present study that the double-mutant enamel density was significantly lower in the regions that represent late maturation-, maturation- and secretory-stage enamel development in wild-type mandibular incisors. However, the “maturation” and “secretory” enamel microstructures in double-mutant animals resembled those observed in wild-type secretory and/or pre-secretory stages. Elemental composition analysis revealed a lack of mineral deposition and an accumulation of carbon and chloride in double-mutant enamel. Deletion of Slc26a1 and Slc26a7 did not affect the stage-specific morphology of the enamel organ. Finally, compensatory expression of pH regulator genes and ion transporters was detected in maturation-stage enamel organs of double-mutant animals when compared to wild-type. Combined with the findings from our previous study, these data indicate the involvement of SLC26A1and SLC26A7 as key ion transporters in the pH regulatory network during enamel maturation.

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

“…Accordingly, we investigated acid-base status in our patients, but all individuals homozygous for SLC26A7 mutations showed normal serum electrolytes and renal function (Supplemental Table 3), with no clinical evidence of achlorhydria. Recent data also support a role for rodent Slc26a7 in dental enamel formation (7); however, our patients did not exhibit abnormal dentition.…”

“…It also localizes to the basolateral membrane of gastric parietal cells and may either facilitate HCO 3 efflux or function as a Clchannel, regulating gastric acid secretion (14,15,3) in agreement with our localization of Slc26a7 protein to both intracellular and basal membrane compartments in thyroid follicular cells. Additionally, Slc26a7 contributes to maintenance of the pH regulatory network during maturation of murine tooth enamel (7). With documented distal renal tubular acidosis and gastric achlorhydria in Slc26a7-null mice, we found no overt renal acid-base abnormalities in our homozygous SLC26A7-mutant patients in the healthy state, but cannot exclude its role when homeostasis is perturbed, analogous to the renal role of pendrin during systemic metabolic alkalosis (16).…”

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

“…membrane of gastric parietal cells and may either facilitate HCO 3 efflux or function as a Clchannel, regulating gastric acid secretion (14,15,3) in agreement with our localization of Slc26a7 protein to both intracellular and basal membrane compartments in thyroid follicular cells. Additionally, Slc26a7 contributes to maintenance of the pH regulatory network during maturation of murine tooth enamel (7). With documented distal renal tubular acidosis and gastric achlorhydria in Slc26a7-null mice, we found no overt renal acid-base abnormalities in our homozygous SLC26A7-mutant patients in the healthy state, but cannot exclude its role when homeostasis is perturbed, analogous to the renal role of pendrin during systemic metabolic alkalosis (16).…”

Importance of SLC26 Transmembrane Anion Exchangers in Sperm Post-testicular Maturation and Fertilization Potential

“…Notably, mutant mouse models have been generated for all SLC26 members, and all reproduced the clinical features of the SLC26 human-related diseases when applicable (Liberman et al, 2002; Forlino et al, 2005; Schweinfest et al, 2006; Touré et al, 2007; Dallos et al, 2008; Dror et al, 2010; El Khouri et al, 2018). In addition, studies of members not so far associated with human diseases (SLC26A7 and A11) revealed their functions in various tissues such as kidney, gastro intestinal tract, enamel, vestibular membrane of the cochlea, and brain (Xu et al, 2009; Rahmati et al, 2013, 2016; Kim et al, 2014; Yin et al, 2017), predicting that further investigations might lead to the identification of novel SLC26 gene mutations associated with pathophysiological conditions in humans (Table 1). Lastly SLC26 function may be critical for cystic fibrosis condition (CF; MIM 219700), a disease which is due to mutations in CFTR, and characterized by general defective electrolyte transport, chronic lung infections and inflammation, respiratory failure, digestive symptoms and male infertility (i.e., congenital bilateral absence of the vas deferens).…”