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Article ; Online: Inherited cataracts: Genetic mechanisms and pathways new and old.

Shiels, Alan / Hejtmancik, J Fielding

2021 Volume 209, Page(s) 108662

Abstract: Cataract(s) is the clinical equivalent of lens opacity and is caused by light scattering either by high molecular weight protein aggregates in lens cells or disruption of the lens microarchitecture itself. Genetic mutations underlying inherited cataract ... ...

Abstract	Cataract(s) is the clinical equivalent of lens opacity and is caused by light scattering either by high molecular weight protein aggregates in lens cells or disruption of the lens microarchitecture itself. Genetic mutations underlying inherited cataract can provide insight into the biological processes and pathways critical for lens homeostasis and transparency, classically including the lens crystallins, connexins, membrane proteins or components, and intermediate filament proteins. More recently, cataract genes have been expanded to include newly identified biological processes such as chaperone or protein degradation components, transcription or growth factors, channels active in the lens circulation, and collagen and extracellular matrix components. Cataracts can be classified by age, and in general congenital cataracts are caused by severe mutations resulting in major damage to lens proteins, while age related cataracts are associated with variants that merely destabilize proteins thereby increasing susceptibility to environmental insults over time. Thus there might be separate pathways to opacity for congenital and age-related cataracts whereby congenital cataracts induce the unfolded protein response (UPR) and apoptosis to destroy the lens microarchitecture, while in age related cataract high molecular weight (HMW) aggregates formed by denatured crystallins bound by α-crystallin result in light scattering without severe damage to the lens microarchitecture.
MeSH term(s)	Animals ; Cataract/congenital ; Cataract/genetics ; Cataract/metabolism ; Connexins/genetics ; Connexins/metabolism ; Crystallins/genetics ; Crystallins/metabolism ; DNA/genetics ; DNA Mutational Analysis ; Disease Models, Animal ; Humans ; Intermediate Filament Proteins/genetics ; Intermediate Filament Proteins/metabolism ; Lens, Crystalline/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mutation
Chemical Substances	Connexins ; Crystallins ; Intermediate Filament Proteins ; Membrane Proteins ; DNA (9007-49-2)
Language	English
Publishing date	2021-06-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2021.108662
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Article ; Online: Understanding the genetic architecture of human retinal degenerations.

Hejtmancik, J Fielding / Daiger, Stephen P

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 8, Page(s) 3904–3906

MeSH term(s)	Humans ; Prevalence ; Retina ; Retinal Degeneration
Language	English
Publishing date	2020-02-07
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1922925117
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Article ; Online: Ophthalmology: Cataracts dissolved.

Hejtmancik, J Fielding

Nature

2015 Volume 523, Issue 7562, Page(s) 540–541

MeSH term(s)	Animals ; Cataract/drug therapy ; Cataract/metabolism ; Female ; Humans ; Lanosterol/pharmacology ; Lanosterol/therapeutic use ; Male ; Protein Aggregates/drug effects ; Protein Aggregation, Pathological/drug therapy
Chemical Substances	Protein Aggregates ; Lanosterol (1J05Z83K3M)
Language	English
Publishing date	2015-07-30
Publishing country	England
Document type	Comment ; Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature14629
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Article ; Online: The Y46D Mutation Destabilizes Dense Packing of the Second Greek Key Pair of Human γC-Crystallin Causing Congenital Nuclear Cataracts.

Vendra, Venkata Pulla Rao / Ostrowski, Christian / Clark, Rebecca / Dyba, Marzena / Tarasov, Sergey G / Hejtmancik, J Fielding

Biochemistry

2023 Volume 62, Issue 12, Page(s) 1864–1877

Abstract: The γ-crystallins are highly expressed structural lens proteins comprising four Greek key motifs arranged in two domains. Their globular structure and short-range spatial ordering are essential for lens transparency. Aromatic residues play a vital role ... ...

Abstract	The γ-crystallins are highly expressed structural lens proteins comprising four Greek key motifs arranged in two domains. Their globular structure and short-range spatial ordering are essential for lens transparency. Aromatic residues play a vital role in stabilizing Greek key folds by forming Greek key or non-Greek key pairs or tyrosine corners. We investigated the effects of the cataractogenic Y46D mutation in the second Greek key pair (Y46-Y51) of human γC-crystallin on its stability and aggregation. Wild-type and Y46D mutant human γC-crystallin were overexpressed in
MeSH term(s)	Humans ; gamma-Crystallins/chemistry ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Tryptophan/genetics ; Cataract/genetics ; Cataract/metabolism ; Mutation
Chemical Substances	gamma-Crystallins ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2023-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.2c00628
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Article ; Online: Biology of Inherited Cataracts and Opportunities for Treatment.

Shiels, Alan / Hejtmancik, J Fielding

Annual review of vision science

2019 Volume 5, Page(s) 123–149

Abstract: Cataract, the clinical correlate of opacity or light scattering in the eye lens, is usually caused by the presence of high-molecular-weight (HMW) protein aggregates or disruption of the lens microarchitecture. In general, genes involved in inherited ... ...

Abstract	Cataract, the clinical correlate of opacity or light scattering in the eye lens, is usually caused by the presence of high-molecular-weight (HMW) protein aggregates or disruption of the lens microarchitecture. In general, genes involved in inherited cataracts reflect important processes and pathways in the lens including lens crystallins, connexins, growth factors, membrane proteins, intermediate filament proteins, and chaperones. Usually, mutations causing severe damage to proteins cause congenital cataracts, while milder variants increasing susceptibility to environmental insults are associated with age-related cataracts. These may have different pathogenic mechanisms: Congenital cataracts induce the unfolded protein response and apoptosis. By contrast, denatured crystallins in age-related cataracts are bound by α-crystallin and form light-scattering HMW aggregates. New therapeutic approaches to age-related cataracts use chemical chaperones to solubilize HMW aggregates, while attempts are being made to regenerate lenses using endogenous stem cells to treat congenital cataracts.
MeSH term(s)	Apoptosis ; Cataract/congenital ; Cataract/genetics ; Cataract/therapy ; Crystallins/genetics ; Eye Diseases, Hereditary/genetics ; Eye Diseases, Hereditary/therapy ; Humans ; Stem Cell Transplantation
Chemical Substances	Crystallins
Language	English
Publishing date	2019-09-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2805730-2
ISSN	2374-4650 ; 2374-4642
ISSN (online)	2374-4650
ISSN	2374-4642
DOI	10.1146/annurev-vision-091517-034346
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Article ; Online: Clinical and genetic risk factors underlying severe consequence identified in 75 families with unilateral high myopia.

Jiang, Yi / Xiao, Xueshan / Sun, Wenmin / Wang, Yingwei / Li, Shiqiang / Jia, Xiaoyun / Wang, Panfeng / Hejtmancik, J Fielding / Zhang, Qingjiong

Journal of translational medicine

2024 Volume 22, Issue 1, Page(s) 75

Abstract: Backgrounds: Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the clinical and genetic spectrum of uHM in a ...

Abstract	Backgrounds: Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the clinical and genetic spectrum of uHM in a large Chinese cohort. Methods: A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis. Results: Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage. Conclusions: Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.
MeSH term(s)	Humans ; Child ; Infant ; Child, Preschool ; Amblyopia/complications ; Mutation ; Pedigree ; Myopia/genetics ; Fluoresceins ; Risk Factors ; DNA Mutational Analysis ; Frizzled Receptors/genetics ; Cytoskeletal Proteins/genetics ; Membrane Proteins/genetics ; Tetraspanins/genetics ; Arthritis ; Connective Tissue Diseases ; Hearing Loss, Sensorineural ; Retinal Detachment
Chemical Substances	Fluoresceins ; FZD4 protein, human ; Frizzled Receptors ; FRMD7 protein, human ; Cytoskeletal Proteins ; Membrane Proteins ; TSPAN12 protein, human ; Tetraspanins
Language	English
Publishing date	2024-01-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-024-04886-5
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Article ; Online: Human γS-Crystallin Mutation F10_Y11delinsLN in the First Greek Key Pair Destabilizes and Impairs Tight Packing Causing Cortical Lamellar Cataract.

Vendra, Venkata Pulla Rao / Ostrowski, Christian / Dyba, Marzena A / Tarasov, Sergey G / Hejtmancik, J Fielding

International journal of molecular sciences

2023 Volume 24, Issue 18

Abstract: Aromatic residues forming tyrosine corners within Greek key motifs are critical for the folding, stability, and order of βγ-crystallins and thus lens transparency. To delineate how a double amino acid substitution in an N-terminal-domain tyrosine corner ... ...

Abstract	Aromatic residues forming tyrosine corners within Greek key motifs are critical for the folding, stability, and order of βγ-crystallins and thus lens transparency. To delineate how a double amino acid substitution in an N-terminal-domain tyrosine corner of the CRYGS mutant p.F10_Y11delinsLN causes juvenile autosomal dominant cortical lamellar cataracts, human γS-crystallin c-DNA was cloned into pET-20b (+) and a p.F10_Y11delinsLN mutant was generated via site-directed mutagenesis, overexpressed, and purified using ion-exchange and size-exclusion chromatography. Structure, stability, and aggregation properties in solution under thermal and chemical stress were determined using spectrofluorimetry and circular dichroism. In benign conditions, the p.F10_Y11delinsLN mutation does not affect the protein backbone but alters its tryptophan microenvironment slightly. The mutant is less stable to thermal and GuHCl-induced stress, undergoing a two-state transition with a midpoint of 60.4 °C (wild type 73.1 °C) under thermal stress and exhibiting a three-state transition with midpoints of 1.25 and 2.59 M GuHCl (wild type: two-state transition with C
MeSH term(s)	Humans ; gamma-Crystallins/chemistry ; Tryptophan/genetics ; Cataract/genetics ; Cataract/metabolism ; Mutation ; Tyrosine/genetics
Chemical Substances	gamma-Crystallins ; Tryptophan (8DUH1N11BX) ; Tyrosine (42HK56048U)
Language	English
Publishing date	2023-09-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241814332
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Article ; Online: Hexokinase 1 and retinitis pigmentosa: insights into the retina and the molecule.

Hejtmancik, J Fielding

Investigative ophthalmology & visual science

2014 Volume 55, Issue 11, Page(s) 7165

MeSH term(s)	DNA/genetics ; Female ; Hexokinase/genetics ; Humans ; Male ; Mutation ; Retina/metabolism ; Retinitis Pigmentosa/genetics
Chemical Substances	DNA (9007-49-2) ; HK1 protein, human (EC 2.7.1.1) ; Hexokinase (EC 2.7.1.1)
Language	English
Publishing date	2014-11-07
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.14-15621
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Article: Molecular Genetic Analysis of Ukrainian Families with Congenital Cataracts.

Jiao, Xiaodong / Viswanathan, Mariia / Bobrova, Nadiia Fedorivna / Romanova, Tatiana Viktorivna / Hejtmancik, J Fielding

Children (Basel, Switzerland)

2022 Volume 10, Issue 1

Abstract: This study was designed to identify the pathogenic variants in five Ukrainian families with autosomal dominant congenital cataracts. Cataracts can be defined broadly as any opacity of the crystalline lens. Lens development is orchestrated by ... ...

Abstract	This study was designed to identify the pathogenic variants in five Ukrainian families with autosomal dominant congenital cataracts. Cataracts can be defined broadly as any opacity of the crystalline lens. Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes, including the lens crystallins, are associated with congenital cataracts and other eye diseases. Whole-exome sequencing identified heterozygous disease-causing variants in five Ukrainian families with autosomal dominant congenital cataracts and cosegregation with cataracts was confirmed using Sanger sequencing. Family 97001 showed a missense variant (c.341T>A: p.L114Q) in HSF4; family 97003 showed a missense variant (c.53A>T: p.N18I) in CRYGA; family 97004 showed a missense variant (c. 82G>A: p.V28M) in GJA3; family 97006 showed a missense variant (c.83C>T: p. P28L) in CRYGC; and family 97008 showed a single-base insertion resulting in a frameshift (c.443_444insA: p. Met148IfsTer51) in PAX6. All five families are associated with congenital cataracts. Overall, we report four novel mutations in HSF4, CRYGA, CRYGC and PAX6, and one previously reported mutation in GJA3 that cause autosomal dominant congenital cataracts.
Language	English
Publishing date	2022-12-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2732685-8
ISSN	2227-9067
ISSN	2227-9067
DOI	10.3390/children10010051
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Article ; Online: Changes in DNA methylation hallmark alterations in chromatin accessibility and gene expression for eye lens differentiation.

Disatham, Joshua / Brennan, Lisa / Jiao, Xiaodong / Ma, Zhiwei / Hejtmancik, J Fielding / Kantorow, Marc

Epigenetics & chromatin

2022 Volume 15, Issue 1, Page(s) 8

Abstract: Background: Methylation at cytosines (mCG) is a well-known regulator of gene expression, but its requirements for cellular differentiation have yet to be fully elucidated. A well-studied cellular differentiation model system is the eye lens, consisting ... ...

Abstract	Background: Methylation at cytosines (mCG) is a well-known regulator of gene expression, but its requirements for cellular differentiation have yet to be fully elucidated. A well-studied cellular differentiation model system is the eye lens, consisting of a single anterior layer of epithelial cells that migrate laterally and differentiate into a core of fiber cells. Here, we explore the genome-wide relationships between mCG methylation, chromatin accessibility and gene expression during differentiation of eye lens epithelial cells into fiber cells. Results: Whole genome bisulfite sequencing identified 7621 genomic loci exhibiting significant differences in mCG levels between lens epithelial and fiber cells. Changes in mCG levels were inversely correlated with the differentiation state-specific expression of 1285 genes preferentially expressed in either lens fiber or lens epithelial cells (Pearson correlation r = - 0.37, p < 1 × 10 Conclusions: Collectively, these results link DNA methylation with control of chromatin accessibility and gene expression changes required for eye lens differentiation. The results also point to a role for DNA methylation in the regulation of transcription factors previously identified to be important for lens cell differentiation.
MeSH term(s)	Cell Differentiation/genetics ; Chromatin/metabolism ; DNA Methylation ; Gene Expression ; Lens, Crystalline/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2022-03-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2462129-8
ISSN	1756-8935 ; 1756-8935
ISSN (online)	1756-8935
ISSN	1756-8935
DOI	10.1186/s13072-022-00440-z
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