Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

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Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore, Mushtaq Ahmed, Hussain Jafri, Yasmin Rashid, Suhaila Al-Bahlani, Sharifa Al Harasi, Jennifer Kirkham, Chris F. Inglehearn, Alan J. Mighell The American Journal of Human Genetics Volume 85, Issue 5, Pages 699-705 (November 2009) DOI: 10.1016/j.ajhg.2009.09.014 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree and Haplotypes of Family P1 Segregating Autosomal-Recessive Hypomature AI Solid circles (female) and squares (male) distinguish affected individuals, the proband being marked with an arrow. Microsatellite marker genotypes used for defining the candidate interval are recorded, the red bars defining the marker haplotype that tracks with the affected status. Each individual included in the whole-genome screen is marked by an asterisk (∗). The American Journal of Human Genetics 2009 85, 699-705DOI: (10.1016/j.ajhg.2009.09.014) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Appearances of Hypomaturation AI in Patients with WDR72 Mutations (A and B) The dentitions of an 8-year-old (A; family P1) and a 7-year-old (B; family P2), illustrating opaque, creamy-brown, discolored enamel that starts to chip away (arrows) from the underlying dentine soon after eruption and leaves an irregular, stained surface. The upper permanent incisor teeth are more markedly affected than are the lower teeth. An anterior open bite, which does not segregate with the AI, is observed in (A) but not (B). (C) The dentition of a 19-year-old member of family P1 illustrates posteruption changes, including loss of surface enamel and marked brown staining, with relative sparing of the lower incisor teeth and cervical enamel. (D) A bitewing radiograph of the individual illustrated in (C), demonstrating gross posteruptive loss of enamel that leaves an irregular surface that is particularly evident on molar teeth (arrow). There is an obvious lack of radiodensity between enamel and dentine in comparison to the inset image of an unerupted tooth from an individual without AI, which has a typical curved crown morphology and enamel (arrow head) that is distinct from the dentine (∗). Note: the inset image is reproduced at approximately two-thirds the size of the affected teeth. The American Journal of Human Genetics 2009 85, 699-705DOI: (10.1016/j.ajhg.2009.09.014) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 WDR72 Mutations and P2, O1, and O2 Family Pedigrees (A) (i) Schematic representation of the annotated genes at the proximal end of the AI-linked interval on chromosome 15q21.3. (ii) Exonic structure (boxes) of WDR72 with the start (ATG) and stop codons marked and with introns represented by lines. The positions of the mutations are marked with arrows. (iii) Representation of the protein structure with approximate positions of the WD40 domains marked. Positions of the mutations in the wild-type protein are marked with arrows. (B) Pedigrees for families P2, O1, and O2 with sequences of the mutations found in each. A diamond shape represents an individual of unknown sex. The American Journal of Human Genetics 2009 85, 699-705DOI: (10.1016/j.ajhg.2009.09.014) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 WDR72 Localization during Mouse Incisor Development in Secretory and Maturation Phases WDR72 immunoreactivity is observed in the enamel organ, with more intense staining in maturation ameloblasts (double arrow in panel B) than in secretory ameloblasts (arrow in panel A). Black arrowheads and the open arrowhead mark the enamel matrix and the enamel space after demineralization, respectively. D and B denote dentine and bone, respectively. Inset in (B) shows negative control in which primary antibody has been omitted. Scale bar represents 100 μm. The American Journal of Human Genetics 2009 85, 699-705DOI: (10.1016/j.ajhg.2009.09.014) Copyright © 2009 The American Society of Human Genetics Terms and Conditions