The Syndrome of Microcornea, Myopic Chorioretinal Atrophy, and Telecanthus (MMCAT) Is Caused by Mutations in ADAMTS18

• Published in: Human mutation Vol. 34; no. 9; pp. 1195 - 1199
• Main Authors: Aldahmesh, Mohammed A., Alshammari, Muneera J., Khan, Arif O., Mohamed, Jawahir Y., Alhabib, Fatimah A., Alkuraya, Fowzan S.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-09-2013; Hindawi Limited
• Subjects: ADAM Proteins - genetics; ADAMTS Proteins; ADAMTS18; Amino Acid Sequence; Child; Chromosomes, Human, Pair 6; Codon, Nonsense; Cornea - abnormalities; Cornea - pathology; Corneal Dystrophies, Hereditary - genetics; Craniofacial Abnormalities - genetics; Exome; Eye Abnormalities - genetics; Eye Abnormalities - physiopathology; Eye Diseases, Hereditary - genetics; Eye Diseases, Hereditary - physiopathology; Humans; Knobloch; linkage; Molecular Sequence Data; Mutation; Mutation, Missense; Myopia, Degenerative - genetics; ocular syndrome; Pedigree; Phenotype; Phylogeny; Saudi Arabia; Sequence Analysis, DNA; Knobloch; exome; linkage; ADAMTS18; ocular syndrome
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22374

ABSTRACT
One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18. Direct sequencing of this gene in four additional probands with the same phenotype revealed three additional homozygous changes in ADAMTS18 including two nonsense mutations. Reassuringly, the autozygomes of all probands overlap on the same chr16q23.1 locus, further supporting the positional mapping of MMCAT to ADAMTS18. ADAMTS18 encodes a member of a family of metalloproteinases that are known for their role in extracellular matrix remodeling, and previous work has shown a strong expression of Adamts18 in the developing eye. Our data suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and myopia.
Alkuraya and colleagues report the genetic etiology of a novel ocular syndrome that is characterized primarily by cataract, myopia and chorioretinal atrophy. Multiple consanguineous families mapped to a single locus on chr16q23.1 in which the authors identified several likely pathogenic mutations in ADAMTS18.