Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome.

Abstract

We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl β-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development.

• Authors: 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
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 94 Issue 5 Pg. 755-9 (May 01 2014) ISSN: 1537-6605 [Electronic] United States
• PMID: 24768550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium-Binding Proteins
• Membrane Proteins
• Muscle Proteins
• Epidermal Growth Factor
• Mixed Function Oxygenases
• ASPH protein, human

Topics

• Amino Acid Sequence
• Animals
• Anterior Eye Segment (abnormalities, enzymology)
• Calcium-Binding Proteins (genetics)
• Craniofacial Abnormalities (enzymology, genetics)
• DNA Mutational Analysis
• Ectopia Lentis (enzymology, genetics)
• Epidermal Growth Factor (chemistry)
• Exome (genetics)
• Female
• Humans
• Iris (abnormalities, enzymology)
• Membrane Proteins (genetics)
• Mice
• Mice, Knockout
• Mixed Function Oxygenases (genetics)
• Molecular Sequence Data
• Muscle Proteins (genetics)
• Pedigree
• Protein Structure, Tertiary (genetics)
• Syndrome
• Young Adult