Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome

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Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome Nisha Patel, Arif O. Khan, Ahmad Mansour, Jawahir Y. Mohamed, Abdullah Al-Assiri, Randa Haddad, Xiaofei Jia, Yong Xiong, André Mégarbané, Elias I. Traboulsi, Fowzan S. Alkuraya The American Journal of Human Genetics Volume 94, Issue 5, Pages 755-759 (May 2014) DOI: 10.1016/j.ajhg.2014.04.002 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Individuals with Traboulsi Syndrome and Mapping of Its Associated Locus (A and B) Pedigree (A) and clinical images (B) of individual 1 from Saudi Arabia. Note the distinct facial features, including a beaked nose, flat cheeks, retrognathia, filtering blebs (black triangles), and patchy iris atrophy. Scleral-fixated intraocular lenses are in place. (C) Shared autozygous ASPH region between the three individuals on chromosome 8. Red denotes differences in calls of homozygous SNPs, revealing the shared haplotype between individuals 2 and 3. (D) Linkage analysis utilizing the three affected individuals revealed a single significant chromosome 8 peak (LOD > 4) corresponding to the ASPH locus. The American Journal of Human Genetics 2014 94, 755-759DOI: (10.1016/j.ajhg.2014.04.002) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of ASPH Mutations that Cause Traboulsi Syndrome (A) DNA sequence chromatogram of the indel observed in individual 1. (B) The upper panel shows a DNA sequence chromatogram with the homozygous missense mutation found in individuals 2 and 3. The lower panel reveals strong conversation of the Arg735 residue, which is altered in these two individuals. (C and D) Schematic showing that mutations found in all three individuals only affect ASPH and not the other two isoforms, Junctin and Junctate. (E) The crystal structure of human ASPH (residues 562–758) shows the overall structure with the zinc ion and the cofactor analog N-oxalylglycine bound at the active site. (F) A zoomed-in view of the active site shows that the Arg735 side chain forms a pair of salt bridges with a carboxylate group of N-oxalylglycine. (G) A model of the p.Arg735Trp variant in ASPH shows that cofactor binding would be disrupted as a result of the loss of the critical salt bridges and potential clashes with the bulky hydrophobic side chain of Trp. The American Journal of Human Genetics 2014 94, 755-759DOI: (10.1016/j.ajhg.2014.04.002) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression of Asph in the Developing Mouse Embryos (A–F) Immunofluorescent staining of ASPH in E10.5 (A), E11.5 (C), and 12.5 (E) frozen eye sections. Note the strong localization in the developing lens at all three stages. Negative controls are shown in (B), (D), and (F). The scale bar in (A) represents 50 μm. (G–H) Whole-mount in situ hybridization of Asph revealed stronger expression in the limbs, snout, and eye (black triangles) of E11.5 (G) and E12.5 (I) mouse embryos than in those of sense controls (H and J). The American Journal of Human Genetics 2014 94, 755-759DOI: (10.1016/j.ajhg.2014.04.002) Copyright © 2014 The American Society of Human Genetics Terms and Conditions