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PITX2 deficiency and associated human disease: insights from the zebrafish model. Hum Mol Genet 2018 05 15;27(10):1675-1695



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Pubmed Central ID




Scopus ID

2-s2.0-85046996401   17 Citations


The PITX2 (paired-like homeodomain 2) gene encodes a bicoid-like homeodomain transcription factor linked with several human disorders. The main associated congenital phenotype is Axenfeld-Rieger syndrome, type 1, an autosomal dominant condition characterized by variable defects in the anterior segment of the eye, an increased risk of glaucoma, craniofacial dysmorphism and dental and umbilical anomalies; in addition to this, one report implicated PITX2 in ring dermoid of the cornea and a few others described cardiac phenotypes. We report three novel PITX2 mutations-c.271C > T, p.(Arg91Trp); c.259T > C, p.(Phe87Leu); and c.356delA, p.(Gln119Argfs*36)-identified in independent families with typical Axenfeld-Rieger syndrome characteristics and some unusual features such as corneal guttata, Wolf-Parkinson-White syndrome, and hyperextensibility. To gain further insight into the diverse roles of PITX2/pitx2 in vertebrate development, we generated various genetic lesions in the pitx2 gene via TALEN-mediated genome editing. Affected homozygous zebrafish demonstrated congenital defects consistent with the range of PITX2-associated human phenotypes: abnormal development of the cornea, iris and iridocorneal angle; corneal dermoids; and craniofacial dysmorphism. In addition, via comparison of pitx2M64* and wild-type embryonic ocular transcriptomes we defined molecular changes associated with pitx2 deficiency, thereby implicating processes potentially underlying disease pathology. This analysis identified numerous affected factors including several members of the Wnt pathway and collagen types I and V gene families. These data further support the link between PITX2 and the WNT pathway and suggest a new role in regulation of collagen gene expression during development.

Author List

Hendee KE, Sorokina EA, Muheisen SS, Reis LM, Tyler RC, Markovic V, Cuturilo G, Link BA, Semina EV


Kathryn Hendee in the CTSI department at Medical College of Wisconsin - CTSI
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anterior Eye Segment
Collagen Type I
Collagen Type V
Eye Abnormalities
Eye Diseases, Hereditary
Gene Editing
Gene Expression Regulation, Developmental
Homeodomain Proteins
Transcription Factors
Wnt Signaling Pathway
Wolff-Parkinson-White Syndrome
Zebrafish Proteins
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0