PITX3 gene

Overview
Microphthalmia, anophthalmia, coloboma (MAC)
Anterior segment dysgenesis
Congenital cataract
References

Overview

Gene (OMIM No.)	PITX3 (#602669)
Function of gene/protein	Protein: paired like homeodomain 3 Regulates other genes by binding to specific DNA regions (transcription factor) A crucial protein involved in lens formation during ocular development Maintains cell division in the developing lens, partially through regulation of *FOXE3* and *PROX1*
Clinical phenotype (OMIM phenotype no.)	Cataract 11, multiple subtypes (#610623) Cataract 11, syndromic, autosomal recessive (#610623) Anterior segment dysgenesis 1, multiple subtypes (#107250)
Inheritance	Autosomal dominant Autosomal recessive
Ocular features	Heterozygous (autosomal dominant) mutations are mainly associated with congenital cataracts and anterior segment dysgenesis (ASD) Congenital cataract — posterior polar or posterior subcapsular subtypes Multiple ASD phenotypes have been reported including Peters anomaly Homozygous (autosomal recessive) variants cause more severe ocular phenotypes Microphthalmia, anophthalmia, coloboma (MAC) spectrum have been reported in addition to cataract and ASD
Systemic features	Two children with homozygous c.650delG mutations from a consaingeneous marriage displayed neurologic features in addition to ocular phenotypes Intellectual disability Developmental delays Choreiform movements Hypertonia Decreased deep tendon reflexes in the lower extremities
Key investigations	B-scan USS to measure axial length to document microphthalmia and detect any posterior abnormalities in congenital cataract cases Electrophysiology TORCH screen for children with congenital cataract Ultrasound biomicroscopy and/or anterior segment OCT to detect anterior segment abnormalities if corneal opacity is present Glaucoma assessment (tonometry, pachymetry, perimetry, gonioscopy if indicated and optic disc imaging) MRI brain and orbit may be indicated if MAC and/or neurologic features are present Systemic assessment with a paediatrician and other relevant specialists if indicated
Molecular diagnosis	Next generation sequencing Targeted gene panels (MAC/congenital cataract/ASD) Whole genome sequencing
Management	Ocular Management of MAC Management of anterior segment dysgenesis Management of congenital cataract Systemic Multidisciplinary approach
Therapies under research	None at present
Further information	OMIM

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References

Berry V, Yang Z, Addison PK, et al. Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J Med Genet. 2004;41(8):e109
Bidinost C, Matsumoto M, Chung D, et al. Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthalmol Vis Sci. 2006;47(4):1274-1280
Cheong SS, Hentschel L, Davidson AE, et al. Mutations in CPAMD8 Cause a Unique Form of Autosomal-Recessive Anterior Segment Dysgenesis. Am J Hum Genet. 2016;99(6):1338-1352
Medina-Martinez O, Shah R, Jamrich M. Pitx3 controls multiple aspects of lens development. Dev Dyn. 2009;238(9):2193-2201
Anand D, Agrawal SA, Slavotinek A, Lachke SA. Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. Hum Mutat. 2018;39(4):471-494
Aldahmesh MA, Khan AO, Mohamed J, Alkuraya FS. Novel recessive BFSP2 and PITX3 mutations: insights into mutational mechanisms from consanguineous populations. Genet Med. 2011;13(11):978-981
Semina EV, Ferrell RE, Mintz-Hittner HA, et al. A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat Genet. 1998;19(2):167-170
Verdin H, Sorokina EA, Meire F, et al. Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics. Orphanet J Rare Dis. 2014;9:26

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Updated on November 30, 2020

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