Molecular Mechanisms of Fuchs and Congenital Hereditary Endothelial Corneal Dystrophies

Malhotra, Deepti; Casey, Joseph R.

doi:10.1007/112_2020_39

Cited by 10 publications

(16 citation statements)

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“…SLC4A11 mutations are responsible for CHED 1 – 3 , HS 5 , 6 , and some cases of late-onset FECD 7 – 9 , 15 . To better understand the role of SLC4A11 protein in corneal dystrophies, we took advantage of a previously characterized slc4a11 −/− mice to perform a transcriptome analysis of adult mouse cornea.…”

Section: Discussionmentioning

confidence: 99%

“…Until recently CHED was considered to only be caused by SLC4A11 mutations but a recent publication has added MPDZ as a rare CHED gene 14 . FECD is also caused by SLC4A11 mutations in addition to mutations of TCF4 , COL8A2 , ZEB1 , AGBL1 and LOXHD1 , genes 15 . HS is now considered a variant of CHED marked by sensorineural deafness in addition to corneal symptoms.…”

Section: Introductionmentioning

confidence: 99%

“…CHED and FECD are complex diseases marked by corneal stromal and epithelial edema due to corneal endothelium dysfunction 15 . Cornea is a multilayer structure, composed of an outer epithelium, followed by a connective tissue layer (Bowman’s layer), the stroma (containing interspersed keratocytes), and the basement membrane, Descemet’s membrane (DM) to which the CEC layer adheres.…”

Section: Introductionmentioning

confidence: 99%

“…This endothelium separates the corneal stroma from the anterior aqueous humor. CECs actively remove osmotically-accumulated fluid from stroma back into aqueous humor, a process known as the “endothelial fluid pump” 15 . The CEC defects observed in CHED and FECD compromise this pump, leading to stromal edema, corneal hazing and vision loss.…”

Section: Introductionmentioning

confidence: 99%

“…Corneal stromal edema and disrupted CEC arrangement 21 , 22 , pathological features concomitantly found in FECD and CHED patients 15 and in the slc4a11 −/− mouse model 23 , suggest that loss of SLC4A11 function underlies the pathology associated with SLC4A11 mutations. Recently, a role of SLC4A11 as a cell adhesion molecule (CAM) contributing to CEC anchorage to the underlying basement membrane, DM, was identified 9 .…”

Section: Introductionmentioning

confidence: 99%

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Altered gene expression in slc4a11−/− mouse cornea highlights SLC4A11 roles

Álvarez

Piché

Aizouki

et al. 2021

Sci Rep

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SLC4A11 is a H+/NH3/water transport protein, of corneal endothelial cells. SLC4A11 mutations cause congenital hereditary endothelial dystrophy and some cases of Fuchs endothelial corneal dystrophy. To probe SLC4A11’s roles, we compared gene expression in RNA from corneas of 17-week-old slc4a11−/− (n = 3) and slc4a11+/+ mice (n = 3) and subjected to RNA sequencing. mRNA levels for a subset of genes were also assessed by quantitative real-time reverse transcription PCR (qRT RT-PCR). Cornea expressed 13,173 genes, which were rank-ordered for their abundance. In slc4a11−/− corneas, 100 genes had significantly altered expression. Abundant slc14a1 expression, encoding the urea transporter UT-A, suggests a significant role in the cornea. The set of genes with altered expression was subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, revealing that alterations clustered into extracellular region, cytoskeleton, cell adhesion and plasma membrane functions. Gene expression changes further clustered into classes (with decreasing numbers of genes): cell fate and development, extracellular matrix and cell adhesion, cytoskeleton, ion homeostasis and energy metabolism. Together these gene changes confirm earlier suggestions of a role of SLC4A11 in ion homeostasis, energy metabolism, cell adhesion, and reveal an unrecognized SLC4A11 role in cytoskeletal organization.

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