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Schematic representation of WT1/ RCN1/ DKFZ p686k1684/PAX6/ ELP4/ DCDC1 on chromosome 11p13 and the relative positions of the microsatellite markers and single nucleotide polymorphism (SNP) used in linkage and real-time quantitative PCR analysis. D presents DKFZ p686k1684. Brown arrows below the each gene indicated the transcription direction for each gene. The region between the two blue vertical lines presents the deleted region (407 Kb) of family 85, the region between the two purple vertical lines presents the deleted region (527 Kb) of family 86.
Source publication
To describe the clinical and genetic findings in two Chinese families with aniridia and other ocular abnormalities.
Two unrelated families were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 (paired box gene 6) gene was perfor...
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To identify the causative paired box 6 (PAX6) mutation in a family with autosomal dominant aniridia.
A family with autosomal dominant aniridia with three affected individuals in two generations was investigated for the causative PAX6 mutation by single strand conformation polymorphism (SSCP) followed by sequencing of genomic DNA from peripheral blo...
To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia.
All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX...
Citations
... [2,4,13]. To date, 30 genomic rearrangements downstream of the PAX6 have been reported in the literature to cause aniridia without neurodevelopment disorders (Fig. 5 Table 3) [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. These deleted regions range from 49 to 1,300 kb, and the distance from the 3' of PAX6 range from 1 to 467 kb. ...
Background
To identify the disease-causing gene in a Chinese family affected with congenital aniridia.
Methods
Patients underwent systematic ophthalmic examinations such as anterior segment photography, fundus photography, optical coherence tomography, and fundus fluorescein angiography. The proband was screened for pathogenic variants by whole exome sequencing (WES) and copy number variant (CNV) analysis. Real-time quantitative PCR (RT-qPCR) was applied to confirm the CNV results. Breakpoints were identified by long-range PCR followed by Sanger sequencing.
Results
All seven members of this Chinese family, including four patients and three normal individuals, were recruited for this study. All patients showed bilateral congenital aniridia with nystagmus, except the son of the proband, who presented with bilateral partial coloboma of the iris. A novel heterozygous deletion (chr11:31,139,019–31,655,997) containing the 3’ regulatory enhancers of the PAX6 gene was detected in this family. We also reviewed the reported microdeletions downstream of PAX6 in patients with aniridia.
Conclusions
We identified a novel microdeletion, 517 kb in size located about 133 kb downstream of the PAX6 gene, responsible for congenital aniridia in this Chinese family, which expands the spectrum of aniridia-associated mutations in PAX6.
... It is difficult to assess the possible effect of DCDC1 dosage imbalance in this case, since no patients carrying a similar aberration or loss-of-function DCDC1 mutations have been described so far. Nevertheless, given that patients with the PAX6 contiguous gene deletion were shown to present more severe vision impairments than individuals carrying PAX6 3 0 rearrangements (Zhang et al., 2011) it is possible that the novel deletion, smaller than lesions reported so far and disrupting only the DCDC1 gene, results in a milder ocular disorder. ...
Aniridia is usually an autosomal dominant, rare disorder characterized by a variable degree of hypoplasia or the absence of iris tissue, with additional ocular abnormalities. Pathogenic variants in the PAX6 gene are associated with aniridia in most patients. However, in up to 30% of individuals, disease results from 11p13 chromosomal rearrangements. Here we present a patient with a clinical diagnosis of partial aniridia born to consanguineous Polish parents. The parents were asymptomatic and ophthalmologically normal. We performed PAX6 sequencing, array comparative genomic hybridization, quantitative real‐time PCR, and whole genome sequencing. aCGH revealed a homozygous deletion of the DCDC1 gene fragment in the patient. The same, but heterozygous deletion, was detected in each of the patient's asymptomatic parents and brother. In the presented family, the signs and symptoms of aniridia are observed only in the homozygous proband. Whole genome sequencing analysis was performed to determine other possible causes of the disease and did not detect any additional or alternative potentially pathogenic variant. We report a novel homozygous deletion located in the 11p13 region, which does not include the PAX6 gene or any known PAX6 enhancers. To our best knowledge, this is the first reported case of a patient presented with isolated aniridia carrying a homozygous microdeletion downstream of the PAX6 gene.
... The failure of any member of the family of elongators, including ELP4, can be associated with different neurological disorders [1,2] . Twenty-five submicroscopic deletions, including the ELP4 gene and the adjacent sequences (excluding the PAX6 gene, the neighboring gene related to aniridia), have been associated with intellectual disability, language development failure, autism spectrum disorder, and epilepsy with aniridia [3][4][5][6][7][8][9] or without aniridia [10] . The ELP4 gene is 273.9 kb in size and encompasses 12 exons. ...
... This CNV was located in a region with recurrent submicroscopic deletions involving the ELP4 gene and subjacent regions (Figure 2). The ELP4 gene has been associated with intellectual disability, language development failure, autism spectrum disorder, epilepsy, and aniridia [3][4][5][6][7][8][9] . Our patient presented intellectual disability and language development failure but not autism spectrum disorder, epilepsy, or aniridia. ...
... Davis et al [4] also reported the case of a patient with aniridia, autism, and intellectual disability due to a 1354 kb deletion involving the ELP4 gene, whereas Bayrakli et al [5] , studied a family with isolated aniridia that showed a deletion of 406 kb involving the ELP4 gene. A study in various members of a family with aniridia showed a 566 kb deletion involving the ELP4 gene [6] , and Zhang et al [7] described a family with bilateral aniridia and congenital cataracts but without intellectual disability or other abnormalities due to a 525 kb deletion involving the ELP4 gene. Simioni et al [8] reported on a child with developmental delay, bilateral strabismus, aniridia, and nystagmus. ...
Background:
We described the main features of an infant diagnosed with facial dysmorphic, language failure, intellectual disability and congenital malformations to strengthen our understanding of the disease. Currently, treatment is only rehabilitation and surgery for cleft lip and palate.
Case summary:
The proband was a 2-years-8-months-old girl. Familial history was negative for congenital malformations or intellectual disability. The patient had microcephaly, upward-slanting palpebral fissures, depressed nasal bridge, bulbous nose and bilateral cleft lip and palate. Brain magnetic resonance imaging showed cortical atrophy and band heterotopia. Her motor and intellectual development is delayed. A submicroscopic deletion in 11p13 involving the elongator acetyltransferase complex subunit 4 gene (ELP4) and a loss of heterozygosity in Xq25-q26.3 were detected.
Conclusion:
There is no treatment for the ELP4 deletion caused by a submicroscopic 11p3 deletion. We describe a second case of deletion of the ELP4 gene without aniridia, which confirms the association between ELP4 gene with several defects and absence of this ocular defect. Additional clinical data in the deletion of the ELP4 gene as cleft palate, facial dysmorphism, and changes at level brain could be associated to this gene or be part of the effect of the recessives genes involved in the loss of heterozygosity region of Xq25-26.3.
... Informed consent was obtained from all patients after a full explanation of the procedures. We enlisted 95 patients with aniridia from 65 unrelated families, including five previously described families [14,15]. Of these families, 39 probands had a family history showing an autosomal dominant inheritance pattern, while the remaining 26 probands were sporadic. ...
... The genomic DNA was extracted using a genomic DNA extraction and purification kit (Vigorous, Beijing, China), following the manufacturer's protocol. Whole exons of the PAX6 gene (including exon 5a) were amplified with 13 pairs of primers, as previously described [15]. PCR assays were carried out using standard reaction mixtures. ...
... The MLPA analyses were carried out using the SALSA MLPA P219-B2 PAX6 probe mix (MRC Holland, Amsterdam, Netherlands) following the manufacturer's protocol. The detailed methods had been previously described [15]. ...
Purpose:
Aniridia is a rare congenital panocular disease caused by mutations in PAX6. The purposes of this study were to clarify the mutation features of PAX6 in a cohort of Chinese patients with aniridia and to describe their clinical characteristics.
Methods:
We recruited 95 patients from 65 unrelated families clinically diagnosed with aniridia. All patients underwent ophthalmic examinations. Sanger sequencing and multiplex ligation probe amplification of PAX6 were performed to detect intragenic variants and copy number variations (CNVs).
Results:
We identified 58 disease-causing mutations in PAX6 in 63 families; the detection rate was 96.9%. The 58 mutations included frameshift indels (27.6%), splice site changes (25.9%), nonsense mutations (20.7%), CNVs (19.0%), missense mutations (3.4%), run-on mutations (1.7%), and a synonymous mutation (1.7%). Clinical examinations revealed that 71 patients had complete or almost complete iris loss, 16 patients showed partial iris loss, and six patients had a full iris but with an abnormal structure.
Conclusions:
The results confirmed that mutations in PAX6 are the predominant cause of aniridia, and the majority are loss-of-function mutations that usually result in classical aniridia. In contrast, missense mutations, run-on mutations, and small numbers of splicing mutations mostly lead to atypical aniridia and an intrafamilial phenotypic variability of iris hypoplasia.
... Therefore, the phenotypes of different PAX6 mutations can be very diverse. PAX6 mutations is characterized by partial or complete absence of the iris accompanied with other ocular abnormalities such as cataract, glaucoma 49 , corneal degeneration 50 , microphthalmia 51 , foveal hypoplasia 52 , optic-nerve malformations 53 . Some individuals with PAX6 mutation developed other systemic diseases such hepatoblastoma, polydactylia 54 . ...
... It was widely belived that truncations of Pax6 can usually cause aniridia phenotype, due to haploinsufficiency 55 . Patients with PAX6 contiguous deletion, may have relatively severe phenotype, including bilateral complete absence of iris and foveal hypoplasia 49 . The two novel PAX6 mutations detected in our study were p.E265fs and p.W114X. ...
Congenital cataract is the most frequent inherited ocular disorder and the most leading cause of lifelong visual loss. The screening of pathogenic mutations can be very challenging in some cases, for congenital cataracts are clinically and genetically heterogeneous diseases. The aim of this study is to investigate the mutation spectrum and frequency of 54 cartaract-associated genes in 27 Chinese families with congenital cataracts. Variants in 54 cataract-associated genes were screened by targeted next-generation sequencing (NGS) and then validated by Sanger sequencing. We identified pathogenic variants in 62.96% (17/27) of families, and over 52.94% (9/17) of these variants were novel. Among them, three are splicing site mutations, four are nonsense mutations, seven are missense mutations, two are frame shift mutations and one is intronic mutation. This included identification of: complex ocular phenotypes due to two novel PAX6 mutations; progressive cortical cataract and lamellar cataract with lens subluxation due to two novel CRYGS mutations. Mutations were also found in rarely reported genes including CRYBA4, CRYBA2, BFSP1, VIM, HSF4, and EZR. Our study expands the mutation spectrum and frequency of genes responsible for congenital cataracts. Targeted next-generation sequencing in inherited congenital cataract patients provided significant diagnostic information.
... The natural progression of AAK can be aggravated by surgical procedures that damage limbal stem area. However, in spite of the growing prevalence of AAK with age [14,22], several cases were reported with no corneal changes in patients with aniridia in older age groups [19,23,24]. In our study as well, LSCM in three adult patients (1A, 1B, 2) reliably showed the presence of POVs in the limbal zone and intact corneal-type epithelial cells (Figs. 1 and 2). ...
Purpose:
The study aimed to evaluate clinical and morphological changes in the limbal palisades of Vogt (POV) at different stages of aniridia-associated keratopathy (AAK) and to assess possible utility of anterior segment optical coherence tomography (AS-OCT) for the visualization of limbal progenitor structures as it correlates to laser scanning confocal microscopy (LSCM) data.
Methods:
The study involved 32 patients (59 eyes) with congenital aniridia. AAK stage was defined based on biomicroscopy. Assessment of limbal zone and detection of POVs in identical areas was performed by LSCM (HRT3) and AS-OCT (RTVue XR Avanti) using 3D Cornea (En Face mode) and Cornea Cross Line protocols.
Results:
Intact and changed POVs were found in 8/8 stage 0 eyes, in 1/21 stage I and 2/13 stage II eyes. Spearman's correlation coefficient in assessing the consistency of the POV diagnostic results by LSCM and AS-OCT for the inferior limbus was rS = 0.85 (P < 0.05), for the superior limbus - rS = 0.53 (P < 0.05). AS-OCT was less sensitive for detection of partially present POVs in superior limbus. The negative correlation between AAK stage and POV preservation was determined (rS = -0.5, P < 0.05). There was no correlation between AAK stage and patient age (rS = 0.235, P = 0.209). Three patients with PAX6 3' deletion showed stage 0 AAK with intact or slightly disturbed POVs morphology and transparent cornea.
Conclusion:
AS-OCT may be an additional diagnostic tool for POV visualization in vivo in aniridic patients. Its diagnostic accuracy is subject to selection of anatomic region, nystagmus and the degree of POV degradation.
... The PAX6 gene encodes a transcription factor with a highly conserved homeodomain that is important for eye development. Its mutations result in autosomal-dominant aniridia, a syndrome including cataracts (Zhang et al., 2011). ...
Neonatal cataracts remain the most common cause of visual loss in children worldwide and have diverse, often unknown, etiologies. This review summarizes current knowledge about the detection, treatment, genetics, risk factors, and molecular mechanisms of congenital cataracts. We emphasize significant progress and topics requiring further study in both clinical cataract therapy and basic lens research. Advances in genetic screening and surgical technologies have improved the diagnosis, management, and visual outcomes of affected children. For example, mutations in lens crystallins and membrane/cytoskeletal components that commonly underlie genetically inherited cataracts are now known. However, many questions still remain regarding the causes, progression, and pathology of neonatal cataracts. Further investigations are also required to improve diagnostic criteria for determining the timing of appropriate interventions, such as the implantation of intraocular lenses and postoperative management strategies, to ensure safety and predictable visual outcomes for children. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc.
... In Saccharomyces cerevisiae, deletions of the individual genes that encode the Elongator subcomplex Elp4-6 revealed that only the ELP5 gene is essential for growth (Krogan and Greenblatt, 2001). However, the mammalian ELP4 gene was recently implicated in rolandic epilepsy (Strug et al., 2009) and the eye anomaly aniridia (Crolla and van Heyningen, 2002;Kleinjan et al., 2002;Zhang et al., 2011). In yeast, the Elongator complex functions as a histone acetyltransferase (HAT) complex that was related to the hyper-phosphorylated elongating form of RNA polymerase II (Glatt et al., 2012). ...
The Saccharomyces cerevisiae Elongator complex consisting of the six Elp1-Elp6 proteins has been proposed to participate in three distinct cellular processes: transcriptional elongation, polarized exocytosis and formation of modified wobble uridines in tRNA. In this study, we investigated the function of BcElp4 in Botrytis cinerea, which is homologous to S. cerevisiae Elp4. A bcelp4 deletion mutant was significantly impaired in vegetative growth, sclerotia formation and melanin biosynthesis. This mutant exhibited decreased sensitivity to osmotic and oxidative stresses as well as cell way-damaging agent. Pathogenicity assays revealed that BcElp4 is involved in the virulence of B. cinerea. In addition, the deletion of bcelp4 led to increased aerial mycelia development. All these defects were restored by genetic complementation of the bcelp4 deletion mutant with the wild-type bcelp4 gene. The results of this study indicated that BcElp4 is involved in regulation of vegetative development, various environmental stress response and virulence in B. cinerea.
... 9 MLPA analysis revealed large deletions affecting PAX6 and/or neighboring genes in 30 probands including 24 sporadic and 6 familial cases (n = 12 patients); 17 different deletions ranging from at least 7.5 Mb to 3 kb were detected and designated Del1-Del17 The non-WAGR patients showed similar defects to those with truncating mutations, which is consistent with other reports. 10 The only deletion outside the coding region of PAX6 was at least~350 kb deletion Del8 that removed part of the PAX6 3 0 -regulatory region, in addition to ELP4 and DCDC1 genes; this deletion was detected in 9 probands with aniridia (Del8; Figure 1). Thus far, at least 15 similar cases have been reported in different populations, 11 suggesting this is a common diseasecausing mechanism. ...
... Previous studies showed that these deletions prevent normal PAX6 expression through disruption of the important cis-distal regulatory region. 10 In one of the familial cases, 06.03, the proband's mother showed subtle iris hypoplasia but did not harbor Del8, identified in the proband. This case represents another example of putative mosaicism. ...
... Естественное течение АК может усугубиться выполнением хирургических вмешательств, повреждающих лимбальную стволовую зону. Однако, несмотря на увеличивающуюся долю АК с возрастом, в литературе описаны случаи отсутствия признаков роговичных изменений у аниридийных пациентов в старших возрастных группах [13][14][15]. Так, в ходе исследования у 3 пациентов (1А, 1В, 2) с 3´делецией на уровне гена ELP4 нами были верифицированы сохранные и несколько измененные прогениторные структуры лимбальной зоны (см. рис. ...
Aim:
to investigate the possible use of anterior segment optical coherence tomography (AS-OCT) and laser scanning confocal microscopy (LSCM) for visualization of limbal progenitor structures and epithelial changes at different stages of aniridia-associated keratopathy (AAK) and to analyze genotype-phenotype correlations of corneal damage.
Material and methods:
Thirty-four patients (63 eyes) with congenital aniridia (CA) were subjected to epithelial cell density measurement in the central cornea as well as epithelial surface assessment with limbal palisades of Vogt (POV) detection in the corresponding sites of the two corneas. For that, LSCM (HRT3) and AS-OCT (RTVue XR Avanti) were performed. Central corneal and epithelial thicknesses were measured using the Pachymetry protocol.
Results:
There has been found an increase in the central corneal thickness (CCT) of CA patients, which correlated with the stage of AAK, and a decrease in the central epithelial thickness as compared with healthy subjects (p<0.05). The difference between the basal and wing epithelial cells density in eyes with stages I and II AAK and normal cells density at stage 0 AAK was statistically significant (p<0.05). Intact or disturbed POV were detected in all patients with PAX6 3' deletion. At that, AS-OCT findings highly agreed with LSCM images for both the inferii (rS=0.85, p<0.05) and superior limbi (rS=0.53, p<0.05). A negative correlation was established between the stage of AAK and in vivo morphology of POV (rS=-0.5, p<0.05). However, no correlation was found between the stage of AAK and patient's age (rS=0.169, p=0.174).
Conclusion:
AS-OCT and LSCM are both important diagnostic tools for corneal surface monitoring in patients with limbal stem cells deficiency.
