title: Variants in TRIM44 Cause Aniridia by Impairing PAX6 Expression.
abstract: Congenital aniridia is a genetic disorder that manifests as iris hypoplasia and other associated ocular complications. Mutations in the paired box 6 (PAX6) gene are considered the major cause of aniridia. In this study, we identified four mutations exclusively presented in aniridia patients from a four-generation Chinese pedigree, including two single nucleotide substitutions in the 3'UTR of PAX6 (NM_000280.4:c.[*76G>A; *2977C>A]) and two missense mutations in tripartite motif containing 44 (TRIM44, NM_017583.4:c.[191C>A; 463G>A]), which lead to amino acid changes p.S64Y and p.G155R, respectively. Bioinformatic analyses revealed that the two 3'UTR mutations of PAX6 disrupted microRNA binding motifs in the wildtype 3'UTR sequence. Luciferase reporter assay and Western blotting with predicted microRNAs showed that the two 3'UTR mutations could only increase or have no effect on the expression of PAX6. Therefore, they would not be the cause of aniridia that resulted from PAX6 deficiency. Instead, we found that overexpression of TRIM44 significantly reduced the expression of PAX6 in human lens epithelial cells, and the p.G155R mutant exhibited much stronger effect than the wildtype form. We conclude that inhibition of PAX6 expression by mutant TRIM44 is a novel pathogenic mechanism for aniridia.
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Xibo
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Qin
authors.affiliation: Institute of Cardiovascular Research, Luzhou Medical College, Luzhou, China.
authors.forename: Guilan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Research, Luzhou Medical College, Luzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Linghan
authors.initials: L
authors.lastname: Gao
authors.affiliation: Institute of Cardiovascular Research, Luzhou Medical College, Luzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Functional Laboratory of Medicine, Luzhou Medical College, Luzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ouyang
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Institute of Cardiovascular Research, Luzhou Medical College, Luzhou, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
mesh_terms: D020413:3' Untranslated Regions; D015783:Aniridia / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D008040:Genetic Linkage; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D000070584:Tripartite Motif Proteins
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; C540677:TRIM44 protein, human; D000070584:Tripartite Motif Proteins
keywords: 3′ untranslated region; PAX6; TRIM44; aniridia; luciferase; microRNA