Rescue of the Congenital Hereditary Endothelial Dystrophy Mouse Model by Adeno-Associated Virus–Mediated Slc4a11 Replacement

Shyam, Rajalekshmy; Ogando, Diego G.; Kim, Edward T.; Murugan, Subashree; Choi, Moonjung; Bonanno, Joseph A.

doi:10.1016/j.xops.2021.100084

Cited by 5 publications

(2 citation statements)

References 34 publications

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“…Specific non-steroidal anti-inflammatory drugs are being investigated for correcting SLC4A11 -specific mutant effects [ 13 ]. The SLC4A11 mutational spectrum can help to develop medicinal approaches and regenerative medicine, such as Gene Therapy (GT) or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based gene editing, [ 14 – 16 ]. Also showed in our recent publication on corneal [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

Salman

Verma

Chaurasia

et al. 2022

Orphanet J Rare Dis

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Background Congenital hereditary endothelial dystrophy (CHED) is a rare form of corneal dystrophy caused by SLC4A11 gene variations. This study aims to find the genetic alterations in SLC4A11, in two Indian familial CHED cases with affected members n = 3 and n = 2 respectively and five sporadic CHED cases using direct sequencing, followed by in silico analysis and characterization of the identified variants. Results All three affected members of the first CHED family were identified with a novel homozygous c.1514C > G (p.Ser489Trp) variation while second family showed presence of a compound heterozygous variation c.529A > C (p.Arg161Arg) + c.2461insT (p.Val805fs). Among five sporadic cases, two showed novel changes, homozygous c.1487G > T (p.Ser480Ile) and c.620-2A > G, while the other one had previously reported homozygous c.2653C > T (p.Arg869Cys) variation. The remaining two cases did not reveal the presence of SLC4A11-related pathogenic variations. The identified variations were excluded from the Indian control (n = 80). In silico analysis using homology-based protein modeling and pathogenicity prediction tools, which revealed these alterations as pathogenic, changing their protein stability, local flexibility, residue contact clashes, and the hydrogen bond interactions. Conclusions This study contributed to the CHED mutational spectrum, adding four novel variations and confirming a previously reported one. It demonstrates different type of variations in CHED cases, including coding, non-coding, homozygous, synonymous, and compound heterozygous variations. The identified variations revealed different degrees of pathogenic effects in silico. Moreover, two sporadic cases could not be identified with pathogenic variation emphasizing the involvement of other genes or genetic mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02521-4.

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Section: Introductionmentioning

confidence: 99%

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

Salman

Verma

Chaurasia

et al. 2022

Orphanet J Rare Dis

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“…Wes immunoassay was carried out since it is challenging to obtain sufficient total protein from corneal endothelial peelings to conduct traditional western blots. Our lab has used this approach in several recent studies to quantify changes in protein expression ( Ogando et al, 2021 ; Shyam et al, 2021 ; Shyam et al, 2022 ; Ogando and Bonanno, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress

Shyam

Ogando

Bonanno

2022

Front. Cell Dev. Biol.

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Recent studies from Slc4a11−/− mice have identified glutamine-induced mitochondrial dysfunction as a significant contributor toward oxidative stress, impaired lysosomal function, aberrant autophagy, and cell death in this Congenital Hereditary Endothelial Dystrophy (CHED) model. Because lysosomes are derived from endoplasmic reticulum (ER)—Golgi, we asked whether ER function is affected by mitochondrial ROS in Slc4a11 KO corneal endothelial cells. In mouse Slc4a11−/− corneal endothelial tissue, we observed the presence of dilated ER and elevated expression of ER stress markers BIP and CHOP. Slc4a11 KO mouse corneal endothelial cells incubated with glutamine showed increased aggresome formation, BIP and GADD153, as well as reduced ER Ca2+ release as compared to WT. Induction of mitoROS by ETC inhibition also led to ER stress in WT cells. Treatment with the mitochondrial ROS quencher MitoQ, restored ER Ca2+ release and relieved ER stress markers in Slc4a11 KO cells in vitro. Systemic MitoQ also reduced BIP expression in Slc4a11 KO endothelium. We conclude that mitochondrial ROS can induce ER stress in corneal endothelial cells.

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Regulation of Corneal Endothelial Function

Bonanno,

Srinivas

2024

Reference Module in Neuroscience and Biobehavioral Psychology

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Rescue of the Congenital Hereditary Endothelial Dystrophy Mouse Model by Adeno-Associated Virus–Mediated Slc4a11 Replacement

Cited by 5 publications

References 34 publications

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress

Regulation of Corneal Endothelial Function

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