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Variants in TRIM44 Cause Aniridia by Impairing PAX6 Expression
Author(s) -
Zhang Xibo,
Qin Gang,
Chen Guilan,
Li Tao,
Gao Linghan,
Huang Li,
Zhang Ying,
Ouyang Ke,
Wang Yuqi,
Pang Yu,
Zeng Bo,
Yu Ling
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22907
Subject(s) - pax6 , aniridia , biology , mutant , genetics , missense mutation , mutation , gene , ectopic expression , microbiology and biotechnology , wild type , mutagenesis , transcription factor
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.