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

Ryan Chao; Linda Nevin; Pooja Agarwal; Jan Riemer; Xiaoyang Bai; Allen Delaney; Matthew Akana; Nelson JimenezLopez; Tanya Bardakjian; Adele Schneider; Nicolas Chassaing; Daniel F Schorderet; David FitzPatrick; Pui-yan Kwok; Lars Ellgaard; Douglas B Gould; Yan Zhang; Jarema Malicki; Herwig Baier; Anne Slavotinek

doi:10.1371/journal.pone.0010565

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

Ryan Chao, Linda Nevin, Pooja Agarwal, Jan Riemer, Xiaoyang Bai, Allen Delaney, Matthew Akana, Nelson JimenezLopez, Tanya Bardakjian, Adele Schneider, Nicolas Chassaing, Daniel F Schorderet, David FitzPatrick, Pui-yan Kwok, Lars Ellgaard, Douglas B Gould, Yan Zhang, Jarema Malicki, Herwig Baier, Anne Slavotinek

Biomolecular Sciences

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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-injetion 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.

Original language	English
Journal	PLoS ONE
Volume	5
Issue number	5
Pages (from-to)	e10565
Number of pages	14
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0010565
Publication status	Published - 2010

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A Male with Unilateral Microphthalmia...Final published version, 2.45 MB

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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., Ellgaard, L., Gould, D. B., Zhang, Y., Malicki, J., Baier, H., & Slavotinek, A. (2010). A male with unilateral microphthalmia reveals a role for TMX3 in eye development. PLoS ONE, 5(5), e10565. https://doi.org/10.1371/journal.pone.0010565

Chao, R, Nevin, L, Agarwal, P, Riemer, J, Bai, X, Delaney, A, Akana, M, JimenezLopez, N, Bardakjian, T, Schneider, A, Chassaing, N, Schorderet, DF, FitzPatrick, D, Kwok, P, Ellgaard, L, Gould, DB, Zhang, Y, Malicki, J, Baier, H & Slavotinek, A 2010, 'A male with unilateral microphthalmia reveals a role for TMX3 in eye development', PLoS ONE, vol. 5, no. 5, pp. e10565. https://doi.org/10.1371/journal.pone.0010565

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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-injetion 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.",

author = "Ryan Chao and Linda Nevin and Pooja Agarwal and Jan Riemer and Xiaoyang Bai and Allen Delaney and Matthew Akana and Nelson JimenezLopez and Tanya Bardakjian and Adele Schneider and Nicolas Chassaing and Schorderet, {Daniel F} and David FitzPatrick and Pui-yan Kwok and Lars Ellgaard and Gould, {Douglas B} and Yan Zhang and Jarema Malicki and Herwig Baier and Anne Slavotinek",

year = "2010",

doi = "10.1371/journal.pone.0010565",

language = "English",

volume = "5",

pages = "e10565",

journal = "PLoS Computational Biology",

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T1 - A male with unilateral microphthalmia reveals a role for TMX3 in eye development

AU - Chao, Ryan

AU - Nevin, Linda

AU - Agarwal, Pooja

AU - Riemer, Jan

AU - Bai, Xiaoyang

AU - Delaney, Allen

AU - Akana, Matthew

AU - JimenezLopez, Nelson

AU - Bardakjian, Tanya

AU - Schneider, Adele

AU - Chassaing, Nicolas

AU - Schorderet, Daniel F

AU - FitzPatrick, David

AU - Kwok, Pui-yan

AU - Ellgaard, Lars

AU - Gould, Douglas B

AU - Zhang, Yan

AU - Malicki, Jarema

AU - Baier, Herwig

AU - Slavotinek, Anne

PY - 2010

Y1 - 2010

N2 - 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-injetion 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.

AB - 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-injetion 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.

U2 - 10.1371/journal.pone.0010565

DO - 10.1371/journal.pone.0010565

M3 - Journal article

C2 - 20485507

SN - 1932-6203

VL - 5

SP - e10565

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 5

ER -

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

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