Identification of<i>PITX3</i>mutations in individuals with various ocular developmental defects

Seco, Celia Zazo; Plaisancié, Julie; Lupasco, Tatiana; Michot, Caroline; Pechméja, J.; Delanne, Julian; Cottereau, Edouard; Ayuso, Carmen; Cortón, Marta; Calvas, Patrick; Ragge, Nicola; Chassaing, Nicolas

doi:10.1080/13816810.2018.1430243

Cited by 19 publications

(17 citation statements)

References 25 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Along with PITX1 and PITX2, PITX3 is the third gene in the PITX homeobox family and it is essential to the formation of the lens during eye development. There have been 9 PITX3 mutations demonstrated to be associated with several different types of CC in several populations (7,14–23) (Table I). However, in China, there have been few studies on PITX3 mutations.…”

Section: Discussionmentioning

confidence: 99%

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

Meng

Fang

et al. 2019

Mol Med Report

View full text Add to dashboard Cite

The present study aimed to identify the disease-causing gene of a four-generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four-generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co-segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four-generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four-generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene-associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

Meng

Fang

et al. 2019

Mol Med Report

View full text Add to dashboard Cite

show abstract

“…Interestingly, all the frameshift variants reported to date are located in exon 4 (upstream from the OAR domain) and none so far within the homeodomain or the OAR domain-coding regions. Of note, homozygous frameshift mutations of PITX3 have been identified in four consanguineous individuals (Aldahmesh et al 2011a;Bidinost et al 2006;Zazo Seco et al 2018). Three of them presented with a more severe ocular phenotype (complex microphthalmia) than the heterozygous family members (from no ocular phenotype to cataract) (Aldahmesh et al 2011a;Bidinost et al 2006).…”

Section: Pitx3 (Paired Like Homeodomain 3)mentioning

confidence: 99%

“…Individuals with pathogenic heterozygous variants in PITX3 manifest isolated and syndromic congenital cataract, anterior segment disorders, such as Peters' anomaly, posterior embryotoxon and sclerocornea (Aldahmesh et al 2011a;Berry et al 2004;Bidinost et al 2006;Burdon et al 2006;Finzi et al 2005;Liu et al 2017a;Semina et al 1998;Summers et al 2008;Verdin et al 2014). Of note, one patient has been reported with a heterozygous variant in PITX3 and complex microphthalmia associated with autism and teeth anomalies (Zazo Seco et al 2018). Most reported mutations are frameshifts, except for one apparently recurrent missense mutation in exon 2 (c.38G>A p.[Ser13Asn], NM_005029.3) in a patient with congenital cataract (Semina et al 1998) and in a dominant family with Peters' anomaly (Zazo Seco et al 2018).…”

Section: Pitx3 (Paired Like Homeodomain 3)mentioning

confidence: 99%

“…Of note, one patient has been reported with a heterozygous variant in PITX3 and complex microphthalmia associated with autism and teeth anomalies (Zazo Seco et al 2018). Most reported mutations are frameshifts, except for one apparently recurrent missense mutation in exon 2 (c.38G>A p.[Ser13Asn], NM_005029.3) in a patient with congenital cataract (Semina et al 1998) and in a dominant family with Peters' anomaly (Zazo Seco et al 2018). Interestingly, all the frameshift variants reported to date are located in exon 4 (upstream from the OAR domain) and none so far within the homeodomain or the OAR domain-coding regions.…”

Section: Pitx3 (Paired Like Homeodomain 3)mentioning

confidence: 99%

See 1 more Smart Citation

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

View full text Add to dashboard Cite

Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

show abstract

“…Among them, nine patients have presented with glaucoma since the diagnoses or during the follow-ups. After panel sequencing, three reported PAcausal variants (PITX2 NM_001204399: p.Pro64Arg, and PITX3 NM_005029: p.Ala214fs, p.Gly219fs) (Weisschuh et al, 2006;Aldahmesh et al, 2011;Zazo et al, 2018) were found in four patients. The mutation detection rate was 17.4%, and all of them were affected bilaterally.…”

Section: Panel Sequencing Indicated a Mutation Detection Rate Of 174mentioning

confidence: 99%

Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Zhang

Dai

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Peters’ anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA causal genes, PITX2 and PITX3. More importantly, two homozygous mutations (NM_057164: p.Val86Ala and p.Arg689Cys) in the COL6A3 gene (collagen type VI alpha-3 chain) that correlated with the phenotype of type I PA were identified, and then validated by following whole-exome sequencing. The expression profile of the COL6A3 gene in the cornea and the impact of the mutations on protein physiological processing and cellular function were further explored. It was shown that COL6A3 presented relatively high expression in the cornea. The mutant COL6A3 protein was relatively retained intracellularly, and its expression reduced cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response. Taken together, our findings expanded the known genetic spectrum of PA, and provided evidence for the involvement of COL6A3 or collagen VI in ocular anterior segment development, thereby offering new insight for future investigations targeting PA.

show abstract

Identification ofPITX3mutations in individuals with various ocular developmental defects

Abstract: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.

Cited by 19 publications

References 25 publications

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Contact Info

Product

Resources

About