Investigating the Clinical Characteristics and PITX3Mutations of a Large Chinese Family with Anterior Segment Mesenchymal Dysgenesis and Congenital Posterior Polar Cataract

Objective To investigate the clinical characteristics and pathogenic genetic mutations of a Chinese family with anterior segment mesenchymal dysgenesis and congenital posterior polar cataract. Methods Through family investigation, the family members were examined via slit lamp anterior segment imaging and screened for eye and other diseases by eye B-ultrasound. Genetic test was performed on the blood samples of the fourth family generation (23 people) via whole exome sequencing (trio-WES) and Sanger sequencing. Results Among the 36 members in four family generations, there were 11 living cases with different degrees of ocular abnormalities, such as cataracts, leukoplakia, and small cornea. All patients who received the genetic test had the heterozygous frameshift mutation c.640_656dup (p.G220Pfs∗95) on exon 4 of the PITX3 gene. This mutation was cosegregated with the clinical phenotypes in the family and thus might be one of the genetic factors that cause the corresponding ocular abnormalities in this family. Conclusion The congenital posterior polar cataract with or without anterior interstitial dysplasia (ASMD) of this family was inherited in an autosomal dominant manner, and the frameshift mutation (c.640_656dup) in the PITX3 gene was the cause of ocular abnormalities observed in this family. This study is of great significance for guiding prenatal diagnosis and disease treatment.

[1]  C. Kioussi,et al.  Pitx genes in development and disease , 2021, Cellular and Molecular Life Sciences.

[2]  Nikolas Pontikos,et al.  Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts , 2021, Eye.

[3]  R. Ciuluvică,et al.  Congenital cataract – clinical and morphological aspects , 2020, Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie.

[4]  Zhennan Zhao,et al.  A novel mutation in the OAR domain of PITX3 associated with congenital posterior subcapsular cataract , 2019, BMC Medical Genetics.

[5]  Xiujie Zheng,et al.  PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population , 2019, Molecular medicine reports.

[6]  S. Lachke,et al.  Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects , 2018, Human mutation.

[7]  P. Calvas,et al.  Identification of PITX3 mutations in individuals with various ocular developmental defects , 2018, Ophthalmic genetics.

[8]  J. Graw.  From eyeless to neurological diseases. , 2017, Experimental eye research.

[9]  M. Ichikawa,et al.  Expression of Truncated PITX3 in the Developing Lens Leads to Microphthalmia and Aphakia in Mice , 2014, PloS one.

[10]  T. de Ravel,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 , 2014, Orphanet Journal of Rare Diseases.

[11]  P. Carlsson,et al.  Pitx3 directly regulates Foxe3 during early lens development. , 2013, The International journal of developmental biology.

[12]  O. Medina-Martinez.  Focus on molecules: Pitx3. , 2012, Experimental eye research.

[13]  F. Alkuraya,et al.  Novel recessive BFSP2 and PITX3 mutations: Insights into mutational mechanisms from consanguineous populations , 2011, Genetics in Medicine.

[14]  S. Bhattacharya,et al.  A novel 1-bp deletion in PITX3 causing congenital posterior polar cataract , 2011, Molecular vision.

[15]  J. Graw,et al.  Clinical and experimental advances in congenital and paediatric cataracts , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[16]  T. Illig,et al.  The transcription factor PITX3 is associated with sporadic Parkinson's disease , 2009, Neurobiology of Aging.

[17]  G. Gole,et al.  Anterior segment mesenchymal dysgenesis in a large Australian family is associated with the recurrent 17 bp duplication in PITX3 , 2008, Molecular vision.

[18]  E. Sorokina,et al.  Functional analysis of human mutations in homeodomain transcription factor PITX3 , 2007, BMC Molecular Biology.

[19]  P. Khaw,et al.  A review of anterior segment dysgeneses. , 2006, Survey of ophthalmology.

[20]  D. Mackey,et al.  The PITX3 gene in posterior polar congenital cataract in Australia. , 2006, Molecular vision.

[21]  B. Bejjani,et al.  Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. , 2006, Investigative ophthalmology & visual science.

[22]  D. Hyde,et al.  Zebrafish pitx3 is necessary for normal lens and retinal development , 2005, Mechanisms of Development.

[23]  S. Bhattacharya,et al.  Posterior polar cataract is the predominant consequence of a recurrent mutation in the PITX3 gene , 2005, British Journal of Ophthalmology.

[24]  I. Maumenee,et al.  Posterior Polar Cataract: Genetic Analysis of a Large Family , 2005, Ophthalmic genetics.

[25]  S. Bhattacharya,et al.  Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4) , 2004, Journal of Medical Genetics.

[26]  G. Gole,et al.  Autosomal dominant cataracts and Peters anomaly in a large Australian family , 1999, Clinical genetics.

[27]  R. Ferrell,et al.  A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD , 1998, Nature Genetics.

[28]  Huanming Yang,et al.  Whole Exome Sequencing Identifies a Novel Mutation in the PITX3 Gene, Causing Autosomal Dominant Congenital Cataracts in a Chinese Family. , 2017, Annals of clinical and laboratory science.

[29]  E. Stahl.  Anterior Segment Dysgenesis , 2014, International ophthalmology clinics.

[30]  J. Nichols,et al.  Homeodomain protein Pitx3 maintains the mitotic activity of lens epithelial cells , 2009, Mechanisms of Development.

[31]  R. Ferrell,et al.  Variable expressivity of autosomal dominant anterior segment mesenchymal dysgenesis in six generations. , 1982, American journal of ophthalmology.