PUBLICATION

A male with unilateral microphthalmia reveals a role for TMX3 in eye development

Authors
Chao, R., Nevin, L., Agarwal, P., Riemer, J., Bai, X., Delaney, A., Akana, M., JimenezLopez, N., Bardakjian, T., Schneider, A., Chassaing, N., Schorderet, D.F., FitzPatrick, D., Kwok, P.Y., Ellgaard, L., Gould, D.B., Zhang, Y., Malicki, J., Baier, H., and Slavotinek, A.
ID
ZDB-PUB-100525-9
Date
2010
Source
PLoS One   5(5): e10565 (Journal)
Registered Authors
Baier, Herwig, Malicki, Jarema, Nevin, Linda
Keywords
Eyes, Microphthalmia, Morpholino, Larvae, Zebrafish, Retina, Choroid, Embryos
MeSH Terms
  • Animals
  • Anophthalmos/genetics
  • Base Pairing/genetics
  • Base Sequence
  • Coloboma/genetics
  • Coloboma/pathology
  • DNA Mutational Analysis
  • Eye/drug effects
  • Eye/growth & development*
  • Eye/pathology
  • Gene Expression Regulation, Developmental/drug effects
  • Homeodomain Proteins/metabolism
  • Humans
  • In Situ Hybridization
  • Infant
  • LIM-Homeodomain Proteins
  • Larva/drug effects
  • Male
  • Mice
  • Microphthalmos/genetics*
  • Microphthalmos/pathology
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense/pharmacology
  • Organ Size/drug effects
  • Phenotype
  • Protein Disulfide-Isomerases/genetics*
  • Protein Disulfide-Isomerases/metabolism
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Sequence Deletion/genetics
  • Transcription Factors
  • Zebrafish/genetics
PubMed
20485507 Full text @ PLoS One
Abstract
Anophthalmia and microphthalmia are important birth defects, but their pathogenesis remains incompletely understood. We studied a patient with severe unilateral microphthalmia who had a 2.7 Mb deletion at chromosome 18q22.1 that was inherited from his mother. In-situ hybridization showed that one of the deleted genes, TMX3, was expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye. We re-sequenced TMX3 in 162 patients with anophthalmia or microphthalmia, and found two missense substitutions in unrelated patients: c.116G>A, predicting p.Arg39Gln, in a male with unilateral microphthalmia and retinal coloboma, and c.322G>A, predicting p.Asp108Asn, in a female with unilateral microphthalmia and severe micrognathia. We used two antisense morpholinos targeted against the zebrafish TMX3 orthologue, zgc:110025, to examine the effects of reduced gene expression in eye development. We noted that the morphant larvae resulting from both morpholinos had significantly smaller eye sizes and reduced labeling with islet-1 antibody directed against retinal ganglion cells at 2 days post fertilization. Co-injection of human wild type TMX3 mRNA rescued the small eye phenotype obtained with both morpholinos, whereas co-injection of human TMX3(p.Arg39Gln) mutant mRNA, analogous to the mutation in the patient with microphthalmia and coloboma, did not rescue the small eye phenotype. Our results show that haploinsufficiency for TMX3 results in a small eye phenotype and represents a novel genetic cause of microphthalmia and coloboma. Future experiments to determine if other thioredoxins are important in eye morphogenesis and to clarify the mechanism of function of TMX3 in eye development are warranted.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes