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.

...PLoS One plos plosone PLoS ONE 1932-6203 Public Library of Science San Francisco, USA 20485507 2868029 09-PONE-RA-14768 10.1371/journal.pone.0010565 Research Article Developmental Biology/Organogenesis Genetics and Genomics/Disease Models Genetics and Genomics/Gene Discovery Genetics and Genomics/Genetics of Disease Genetics and Genomics/Medical Genetics Developmental Biology/Organogenesis Genetics and Genomics/Medical Genetics A Male with Unilateral Microphthalmia Reveals a Role for TMX3 in Eye Development TMX3 and Microphthalmia Chao Ryan 1 Nevin Linda 2 Agarwal Pooja 3 Riemer Jan 4 Bai Xiaoyang 5 Delaney Allen 6 Akana Matthew 7 JimenezLopez Nelson 1 Bardakjian Tanya 8 Schneider Adele 8 Chassaing Nicolas 9 Schorderet Daniel F. 10 FitzPatrick David 11 Kwok Pui-yan 7 Ellgaard Lars 4 Gould Douglas B. 5 Zhang Yan 12 Malicki Jarema 12 Baier Herwig 2 Slavotinek Anne 1 * 1 Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California

... credited. 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. Introduction Birth defects affect an estimated 120,000 (1 in 33) babies born in the United States each year, and are the leading cause of death in the first year of life [1] . Anophthalmia is characterized by the absence of an eye or the presence of a

... diaphragmatic hernia patients identified a novel 18q22.1 deletion using the Affymetrix GeneChip Human Mapping 100K Set in a patient with unilateral microphthalmia and right-sided diaphragmatic hernia [16] . The following work describes our evaluation of the genes contained within this deletion: Cadherin 19, type 2 preprotein, ( CDH19 ; Accession number NM_021153), Thioredoxin domain-containing 10 ( TMX3 , also known as TXNDC10 , Accession number NM_019022), Dermatan sulfate epimerase-like ( DSEL ; Accession

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Gene: TMX3 - thioredoxin-related transmembrane protein 3 - (NCBI)

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