FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

Khan, Shahid Y.; Vasanth, Shivakumar; Kabir, Firoz; Gottsch, John D.; Khan, Arif O.; Chaerkady, Raghothama; Lee, Mei-Chong Wendy; Leitch, Carmen C.; Ma, Zhiwei; Laux, Julie; Villasmil, Rafael; Khan, Shaheen N.; Riazuddin, Sheikh; Akram, Javed; Cole, Robert N.; Talbot, C. Conover; Pourmand, Nader; Zaghloul, Norann A.; Hejtmancik, J. Fielding

doi:10.1038/ncomms10953

Cited by 36 publications

(25 citation statements)

References 41 publications

(44 reference statements)

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“…Genomic DNA was extracted from white blood cells as previously described. 17 Exclusion analysis, two-point logarithm of odds (LOD) score calculations, and bi-directional Sanger sequencing were completed as previously described, along with the sequences of the primer pairs used for Sanger sequencing. 14…”

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A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

et al. 2016

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Glaucoma is the second leading cause of blindness, affecting ~65 million people worldwide. We identified and ascertained a large cohort of inbred families with multiple individuals manifesting cardinal symptoms of primary congenital glaucoma (PCG) to investigate the etiology of the disease at a molecular level. Ophthalmic examinations, including slit-lamp microscopy and applanation tonometry, were performed to characterize the causal phenotype and confirm that affected individuals fulfilled the diagnostic criteria for PCG. Subsequently, exclusion analysis was completed with fluorescently labeled short tandem repeat markers, followed by Sanger sequencing to identify pathogenic variants. Exclusion analysis suggested linkage to the CYP1B1 locus, with positive two-point logarithm of odds scores in 23 families, while Sanger sequencing identified a total of 11 variants, including two novel mutations, in 23 families. All mutations segregated with the disease phenotype in their respective families. These included the following seven missense mutations: p.Y81N, p.E229K, p.R368H, p.R390H, p.W434R, p.R444Q and p.R469W, as well as one nonsense mutation, p.Q37*, and three frameshift mutations, p.W246Lfs81*, p.T404Sfs30* and p.P442Qfs15*. In conclusion, we identified a total of 11 mutations, reconfirming the genetic heterogeneity of CYP1B1 in the pathogenesis of PCG. To the best of our knowledge, this is the largest study investigating the contribution of CYP1B1 to the pathogenesis of PCG in the Pakistani population.

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A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

et al. 2016

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“…In patients with Peter’s Anomaly, DNAJB1 transcripts were shown to be a target of FOXE3. Zebrafish deficient in dnajb1a (the zebrafish DNAJB1 ortholog) were used to confirm the role of DNAJB1 in this condition [94]. It is anticipated that gclc- depleted zebrafish will similarly provide unique insights into human lens development and thereby provide benefits for human health.…”

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confidence: 99%

Gclc deletion in surface-ectoderm tissues induces microphthalmia

Thompson

Chen

Philippe

et al. 2019

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Glutamate cysteine ligase catalytic subunit (Gclc) is the catalytic subunit for the glutamate-cysteine ligase (Gcl) enzyme. Gcl catalyzes the rate limiting step in glutathione (GSH) synthesis. Gclc is highly expressed in the developing eye. To define the regulatory role of Gclc in eye development, we developed a novel, Le-Cre transgene-driven, Gclc knockout mouse model. Gclc f/f /Le-Cre Tg/mice present with deformation of the retina, cornea, iris, and lens, consistent with a microphthalmia phenotype. Controlling for the microphthalmia phenotype of Gclc wt/wt /Le-Cre Tg/mice revealed that Gclc f/f /Le-Cre Tg/mice have a more severe microphthalmia phenotype. Thus, the loss of Gclc expression exacerbates the microphthalmia phenotype in Le-Cre mice.Gclc f/f /Le-Cre Tg/eyes present with reduced retinal and lens epithelium proliferation and increased lens cell death. Imaging mass spectrometry of ocular tissues revealed changes in the intensity and distribution of several lipid species and proteins in the retina and corneas of Gclc f/f /Le-Cre Tg/eyes. Lastly, using splice-blocking morpholinos and CRISPR/Cas9, we created two gclc knockdown zebrafish models, both of which display a microphthalmia phenotype. Combined, the mouse and zebrafish results indicate that, in chordates, Gclc has a conserved role in regulating eye development. In summary, these novel animal models are useful tools for elucidating the mechanisms involved in microphthalmia development.≈ 11% of the cases [1]. Currently, there is no cure for the severe loss of vision associated with microphthalmia. While surgical treatments exist, they only address the cosmetic abnormalities associated with microphthalmia [15]. However, recent research demonstrating the efficacy of nonsense suppression (inhibiting the effect of a nonsense mutation by pharmacologically increasing the likelihood of a near cognate aminoacyl-tRNA substitution) to rescue lens development when administered postnatally in a Pax6-deficient mouse model has provided hope that treatments for microphthalmia can be developed [16]. Clearly, a more complete understanding of the mechanisms regulating lens development should accelerate the discovery of preventative strategies and/or novel therapeutic treatments for microphthalmia. Glutathione (GSH), an intracellular antioxidant, is highly abundant in the eye, with concentrations of 20mM or more occurring in the lens cortex and epithelium [17, 18]. It is important for physiological detoxification of electrophiles and oxidants in the lens cortex and epithelium [19]. Through these functions, GSH maintains lens clarity and, as such, a decline in GSH levels is associated with cataract development [20, 21]. GSH biosynthesis involves a two-step enzymatic process [22] involving glutamate-cysteine ligase (GCL) followed by glutathione synthase (GSS). GCL, the rate limiting step in GSH synthesis, comprises a catalytic subunit (GCLC) and a modifier subunit (GCLM). Impaired GCLC or GCLM function limits GSH synthesis and reduces intracellular GSH concentrations. Th...

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“… 31 Moreover, we recently reported that haploinsufficiency of DNAJB1 , an autophagy-associated cochaperone, results in Peters anomaly. 32 We searched the proteins in the mouse lens proteome and identified 404 autophagy-associated proteins ( Supplementary Table S18 ). Interestingly, proteins involved in autophagy exhibited a relatively higher expression in postnatal lens consistent with the notion that autophagy plays a critical role in lens fiber cell differentiation.…”

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confidence: 99%

Proteome Profiling of Developing Murine Lens Through Mass Spectrometry

Khan

Ali

Kabir

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeWe previously completed a comprehensive profile of the mouse lens transcriptome. Here, we investigate the proteome of the mouse lens through mass spectrometry–based protein sequencing at the same embryonic and postnatal time points.MethodsWe extracted mouse lenses at embryonic day 15 (E15) and 18 (E18) and postnatal day 0 (P0), 3 (P3), 6 (P6), and 9 (P9). The lenses from each time point were preserved in three distinct pools to serve as biological replicates for each developmental stage. The total cellular protein was extracted from the lens, digested with trypsin, and labeled with isobaric tandem mass tags (TMT) for three independent TMT experiments.ResultsA total of 5404 proteins were identified in the mouse ocular lens in at least one TMT set, 4244 in two, and 3155 were present in all three TMT sets. The majority of the proteins exhibited steady expression at all six developmental time points; nevertheless, we identified 39 proteins that exhibited an 8-fold differential (higher or lower) expression during the developmental time course compared to their respective levels at E15. The lens proteome is composed of diverse proteins that have distinct biological properties and functional characteristics, including proteins associated with cataractogenesis and autophagy.ConclusionsWe have established a comprehensive profile of the developing murine lens proteome. This repository will be helpful in identifying critical components of lens development and processes essential for the maintenance of its transparency.

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FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

Cited by 36 publications

References 41 publications

A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent

Gclc deletion in surface-ectoderm tissues induces microphthalmia

Proteome Profiling of Developing Murine Lens Through Mass Spectrometry

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