title: A male with unilateral microphthalmia reveals a role for TMX3 in eye development.
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.
authors.affiliation: Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Chao
authors.forename: Linda
authors.initials: L
authors.lastname: Nevin
authors.forename: Pooja
authors.initials: P
authors.lastname: Agarwal
authors.forename: Jan
authors.initials: J
authors.lastname: Riemer
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Bai
authors.forename: Allen
authors.initials: A
authors.lastname: Delaney
authors.forename: Matthew
authors.initials: M
authors.lastname: Akana
authors.forename: Nelson
authors.initials: N
authors.lastname: JimenezLopez
authors.forename: Tanya
authors.initials: T
authors.lastname: Bardakjian
authors.forename: Adele
authors.initials: A
authors.lastname: Schneider
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: David
authors.initials: D
authors.lastname: FitzPatrick
authors.forename: Pui-yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Lars
authors.initials: L
authors.lastname: Ellgaard
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jarema
authors.initials: J
authors.lastname: Malicki
authors.forename: Herwig
authors.initials: H
authors.lastname: Baier
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
mesh_terms: D000818:Animals; D000853:Anophthalmos / Q000235:genetics; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D003103:Coloboma / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005123:Eye / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D060850:LIM-Homeodomain Proteins; D007814:Larva / Q000187:drug effects; D008297:Male; D051379:Mice; D008850:Microphthalmos / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D014157:Transcription Factors; D015027:Zebrafish / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D019704:Protein Disulfide-Isomerases; C498879:TMX3 protein, human