A male with unilateral microphthalmia reveals a role for TMX3 in eye development.
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.
Chao
Ryan
R
Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
Nevin
Linda
L
Agarwal
Pooja
P
Riemer
Jan
J
Bai
Xiaoyang
X
Delaney
Allen
A
Akana
Matthew
M
JimenezLopez
Nelson
N
Bardakjian
Tanya
T
Schneider
Adele
A
Chassaing
Nicolas
N
Schorderet
Daniel F
DF
FitzPatrick
David
D
Kwok
Pui-yan
PY
Ellgaard
Lars
L
Gould
Douglas B
DB
Zhang
Yan
Y
Malicki
Jarema
J
Baier
Herwig
H
Slavotinek
Anne
A
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
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