Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma.
OBJECTIVE
Microphthalmia, anophthalmia, and coloboma are ocular malformations with a significant genetic component. Rx is a homeobox gene expressed early in the developing retina and is important in retinal cell fate specification as well as stem cell proliferation. We screened a group of 24 patients with microphthalmia, coloboma, and/or anophthalmia for RX mutations.


METHODS
We used standard PCR and automated sequencing techniques to amplify and sequence each of the three RX exons. Patients' charts were reviewed for clinical information. The pathologic impact of the identified sequence variant was analyzed by computational methods using PolyPhen and PMut algorithms.


RESULTS
In addition to the polymorphisms we identified a single patient with coloboma having a heterozygous nucleotide change (g.197G>C) in the first exon that results in a missense mutation of arginine to threonine at amino acid position 66 (R66T). In silico analysis predicted R66T to be a deleterious mutation.


CONCLUSIONS
Sequence variations in RX are uncommon in patients with congenital ocular malformations, but may play a role in disease pathogenesis. We observed a missense mutation in RX in a patient with a small, typical chorioretinal coloboma, and postulate that the mutation is responsible for the patient's phenotype.
London
Nikolas J S
NJ
Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Kessler
Patricia
P
Williams
Bryan
B
Pauer
Gayle J
GJ
Hagstrom
Stephanie A
SA
Traboulsi
Elias I
EI
D019943:Amino Acid Substitution; D000853:Anophthalmos / Q000235:genetics*; D001483:Base Sequence; D003103:Coloboma / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005654:Fundus Oculi; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008850:Microphthalmos / Q000235:genetics*; D008969:Molecular Sequence Data; D014157:Transcription Factors / Q000235:genetics*
D005136:Eye Proteins; D018398:Homeodomain Proteins; C486393:RAX protein, human; D014157:Transcription Factors