Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome.
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.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Nisha
N
Patel
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia.
Arif O
AO
Khan
Department of Ophthalmology, American University of Beirut, Beirut 1107-2020, Lebanon.
Ahmad
A
Mansour
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Jawahir Y
JY
Mohamed
Division of Anterior Segment, King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia.
Abdullah
A
Al-Assiri
Department of Ophthalmology, American University of Beirut, Beirut 1107-2020, Lebanon.
Randa
R
Haddad
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Xiaofei
X
Jia
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Yong
Y
Xiong
Medical Genetics Unit, Faculty of Medicine, Saint Joseph University, Beirut 1104-2020, Lebanon.
André
A
Mégarbané
Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Elias I
EI
Traboulsi
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
Fowzan S
FS
Alkuraya
D000595:Amino Acid Sequence; D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000201:enzymology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004479:Ectopia Lentis / Q000201:enzymology / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000737:chemistry; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007498:Iris / Q000002:abnormalities* / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D013577:Syndrome; D055815:Young Adult
D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D004815:Epidermal Growth Factor; D006899:Mixed Function Oxygenases; C419389:ASPH protein, human