In the current study, we identified the first locus for autosomal dominant OOD and extended the clinical study of a previously described pedigree.
10 Although oto-dental syndrome is a rare condition, several cases and families have now been described.
10 19 20 21 22 23 24 25 26 27 The family described in this report is the only one currently known that has disease with associated ocular features. We significantly extended the pedigree and in particular focused our clinical assessment on ocular features of all eyes examined. New ocular features—microcornea, microphthalmos, lenticular opacity, and lens coloboma—are now included in this phenotype, in addition to the iris and chorioretinal colobomas previously recorded. Furthermore, it is noted that individuals previously described as having normal eyes (IV-7, right eye of III-2;
Fig. 1 ) in fact had marked iris pigment epithelial atrophy on slit lamp examination, which represents the mildest ocular abnormality in the phenotype. Similarly, patient II-5 (deceased) was described historically as having normal eyes, but may also have had mild iris pigment epithelial atrophy. Markedly variable ocular phenotype, throughout the pedigree, is perhaps not surprising in an autosomal dominant condition. However, it is unclear how to explain the marked phenotype asymmetry between eyes in individual patients as a simple inherited genetic defect. Possibly, other genetic or environmental effects may influence disease severity in different eyes.
The disease locus (
OOD1) maps to chromosome 20q13.1. This 12-cM region, flanked by marker loci
D20S108 and
D20S159, now linked to OOD
(Fig. 3) , contains a large number of genes
. One particular candidate,
EYA2, codes for a transcription factor, a class of genes that have been associated with ocular developmental defects. Examples include
PAX2 (ocular coloboma plus renal disease
15 ) and
CHX10 (iris coloboma with microphthalmia
13 ). In addition,
EYA2 is known to be expressed in the eye, ear, and craniofacial mesenchyme very early during development (ninth week after conception) in humans.
29 Other members of the
EYA gene family have been associated with branchio-oto-renal syndrome (
EYA1)
29 and nonsyndromic dominant deafness (
EYA4).
30 We screened all 15
EYA2 coding exons, respective splice sites, and the 5′UTR, but found no disease-associated mutation. Although our results exclude a simple exonic or splice site
EYA2 mutation, a promoter mutation in
EYA2 is still possible.
To narrow the list of other candidate genes mapping to human chromosome 20q13.1, we looked for mouse mutants with phenotypes similar to OOD syndrome. No comparable mouse model has been reported as mapping to the syntenic region of mouse chromosome 2. The fact that ocular coloboma has only been reported in this oto-dental-affected family may complicate the search for the responsible genetic defect. It is possible that the ocular component in this family is caused by a unique mutation in the oto-dental gene not found in other affected families. Alternatively, the eye defect in this family may be due to a contiguous gene defect, possibly affecting EYA2 expression. A third explanation could be that the OOD gene is an entirely different gene from that causing oto-dental dysplasia, but that the gene’s products interact or function within the same biochemical pathway.
Although OOD syndrome is rare, the disease gene may be relevant, not only to this phenotype, but to other diseases affecting the eye, ear, or teeth. Identifying the gene is therefore of importance in our understanding of the development of a wide range of tissues, not just the eye. Certainly, as the only disease entity known to result in abnormally enlarged teeth, the OOD gene will hold an important place in improving our understanding of the genetic control of tooth development.
The authors thank Gerald B. Winter and Jane R. Goodman, Eastman Dental Hospital, London, United Kingdom, and the patients within the family that participated in this study.