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

Autozygosity mapping and clonal sequencing of an Omani family identified mutations in the uncharacterized gene, C4orf26, as a cause of recessive hypomineralized amelogenesis imperfecta (AI), a disease in which the formation of tooth enamel fails. Screening of a panel of 57 autosomal-recessive AI-affected families identified eight further families with loss-of-function mutations in C4orf26. C4orf26 encodes a putative extracellular matrix acidic phosphoprotein expressed in the enamel organ. A mineral nucleation assay showed that the protein's phosphorylated C terminus has the capacity to promote nucleation of hydroxyapatite, suggesting a possible function in enamel mineralization during amelogenesis.