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

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Serval ID
serval:BIB_41E9F009D72C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A male with unilateral microphthalmia reveals a role for TMX3 in eye development.
Journal
Plos One
Author(s)
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., Slavotinek A.
ISSN
1932-6203[electronic], 1932-6203[linking]
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
5
Number
5
Pages
e10565
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
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.
Keywords
Animals, Anophthalmos/genetics, Base Pairing/genetics, Base Sequence, Coloboma/genetics, Coloboma/pathology, DNA Mutational Analysis, Eye/drug effects, Eye/growth & development, Gene Expression Regulation, Developmental/drug effects, Homeodomain Proteins/metabolism, Humans, In Situ Hybridization, Infant, 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, Zebrafish/genetics
Pubmed
Web of science
Open Access
Yes
Create date
14/10/2010 8:08
Last modification date
20/08/2019 13:43
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