Mutations in C4orf26, Encoding a Peptide with In Vitro Hydroxyapatite Crystal Nucleation and Growth Activity, Cause Amelogenesis Imperfecta David A.

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Mutations in C4orf26, Encoding a Peptide with In Vitro Hydroxyapatite Crystal Nucleation and Growth Activity, Cause Amelogenesis Imperfecta David A. Parry, Steven J. Brookes, Clare V. Logan, James A. Poulter, Walid El-Sayed, Suhaila Al-Bahlani, Sharifa Al Harasi, Jihad Sayed, El Mostafa Raïf, Roger C. Shore, Mayssoon Dashash, Martin Barron, Joanne E. Morgan, Ian M. Carr, Graham R. Taylor, Colin A. Johnson, Michael J. Aldred, Michael J. Dixon, J. Tim Wright, Jennifer Kirkham, Chris F. Inglehearn, Alan J. Mighell The American Journal of Human Genetics Volume 91, Issue 3, Pages 565-571 (September 2012) DOI: 10.1016/j.ajhg.2012.07.020 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of a Recessive AI Locus on Chromosome 4q (A) Pedigree of family AI-46. (B) AutoSNPa18 output for chromosome 4 for individuals IV:9 and IV:10 and an equimolar combination of DNA from IV:12, IV:13, and IV:15. Heterozygous SNPs are highlighted in yellow, homozygous SNPs are shown in black, and chromosome position (Mb) is shown on the left. The disease interval is marked between SNPs rs7679122 and rs17030727 (chr4: 69,820,283–101,963,249). The American Journal of Human Genetics 2012 91, 565-571DOI: (10.1016/j.ajhg.2012.07.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Dental Phenotypes Due to C4orf26 Mutations (A) Family AI-46 from Oman. The appearance is within normal limits for the heterozygous (carrier) mother (A.iii) (see III:2 in Figure S1) of the affected individuals (A.i and A.ii) (see IV:13 and IV:12, respectively, in Figure S1). By contrast, all the other clinical images are from individuals with homozygous mutations. The affected enamel is yellowish brown and hypomineralized with partial, mild developmental enamel hypoplasia. The enamel is prone to rapid functional failure with posteruptive volume loss. Dental plaque deposits (→) can be extensive, reflecting difficulties in maintaining good oral hygiene as the teeth fail and become sensitive. (B) Individual II:4 (see Figure S1) from Iraqi family AI-1. A dental radiograph (B.ii) illustrates a near-normal crown morphology for the unerupted permanent upper canine tooth (∗), which is in the process of replacing the almost exfoliated deciduous canine (x). In the permanent canine there is absence of the expected contrast between enamel and dentine radiodensity. These appearances are consistent with enamel hypomineralization. Bitewing radiographs (B.iii) illustrate poor-quality enamel and premature enamel failure involving the occlusal surfaces of permanent (p) and deciduous teeth. Dental restorations (+) are marked. (C) Individual IV:2 (see Figure S1) from Syrian family AI-42. (D) Individual IV:1 (see Figure S1) from Omani family AI-47. (E) Individual II:2 (see Figure S1) from Omani family AI-51. The American Journal of Human Genetics 2012 91, 565-571DOI: (10.1016/j.ajhg.2012.07.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 C4orf26 mutations (A–E) Representative electropherograms for C4orf26 mutations uncovered in AI-affected families. (F) Schematic representation of human C4orf26 protein. Sequence changes found in AI-affected families are marked by vertical arrows. Predicted phosphorylated sites are shown as red circles. Shading indicates the predicted signal peptide (gray), two conserved motifs (green and light blue), and the C-terminal peptide (dark and light blue) used in HA-nucleation experiments. The American Journal of Human Genetics 2012 91, 565-571DOI: (10.1016/j.ajhg.2012.07.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression and Functional Characterization of C4orf26 (A) RT-PCR demonstrating expression of the rat ortholog of C4orf26 in the enamel organ; band identity is confirmed by sequencing. (B) Representative in vitro mineralization data showing the mass of phosphate precipitated with no peptide (negative control), the polyglutamic-acid positive control, and nonphosphorylated and phosphorylated peptides corresponding to the C-terminal 30 residues of C4orf26. Data (n = 6) were analyzed with an unpaired one-tailed Student’s t test. ∗∗∗∗p < 0.0001. The following abbreviation is used: ns, not significant. The American Journal of Human Genetics 2012 91, 565-571DOI: (10.1016/j.ajhg.2012.07.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions