Missense mutation in SLC4A11 in two Pakistani families affected with congenital hereditary endothelial dystrophy (CHED2)

Kaul, Haiba; Suman, Maryam; Khan, Zoya; Ullah, Muhammad Ikram; Ashfaq, Usman Ali; Idrees, Sobia

doi:10.1111/cxo.12276

Cited by 15 publications

(11 citation statements)

References 12 publications

(15 reference statements)

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“…Approximately 94 SLC4A11 mutations have been identified in individuals with CHED. 4,6,9,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Although a large number of these mutations result in SLC4A11 protein misfolding and failure to mature to the plasma membrane, 5,6,[49][50][51] some mutations affect SLC4A11 transporter function without impacting membrane trafficking 17,52,53 or cause aberrant SLC4A11 pre-mRNA splicing and subsequent reduced SLC4A11 expression. 47 Collectively, these observations support the hypothesis that loss of SLC4A11 function is the primary pathogenetic mechanism in CHED rather than mutant SLC4A11 protein misfolding/mislocalization in the endoplasmic reticulum (ER).…”

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confidence: 99%

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

Zhang

Frausto

Chung

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To elucidate the molecular events in solute carrier family 4 member 11 (SLC4A11)-deficient corneal endothelium that lead to the endothelial dysfunction that characterizes the dystrophies associated with SLC4A11 mutations, congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy 4. METHODS. Comparative transcriptomic analysis (CTA) was performed in primary human corneal endothelial cells (pHCEnC) and murine corneal endothelial cells (MCEnC) with normal and reduced levels of SLC4A11 (SLC4A11 KD pHCEnC) and Slc4a11 (Slc4a11 −/− MCEnC), respectively. Validation of differentially expressed genes was performed using immunofluorescence staining of CHED corneal endothelium, as well as western blot and quantitative PCR analysis of SLC4A11 KD pHCEnC and Slc4a11 −/− MCEnC. Functional analyses were performed to investigate potential functional changes associated with the observed transcriptomic alterations. RESULTS. CTA revealed inhibition of cell metabolism and ion transport function as well as mitochondrial dysfunction, leading to reduced adenosine triphosphate (ATP) production, in SLC4A11 KD pHCEnC and Slc4a11 −/− MCEnC. Co-localization of SNARE protein STX17 with mitochondria marker COX4 was observed in CHED corneal endothelium, as was activation of AMPK-p53/ULK1 in both SLC4A11 KD pHCEnC and Slc4a11 −/− MCEnC, providing additional evidence of mitochondrial dysfunction and mitophagy. Reduced Na +-dependent HCO 3 − transport activity and altered NH 4 Cl-induced membrane potential changes were observed in Slc4a11 −/− MCEnC. CONCLUSIONS. Reduced steady-state ATP levels and subsequent activation of the AMPK-p53 pathway provide a link between the metabolic functional deficit and transcriptome alterations, as well as evidence of insufficient ATP to maintain the Na + /K +-ATPase corneal endothelial pump as the cause of the edema that characterizes SLC4A11associated corneal endothelial dystrophies.

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confidence: 99%

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

Zhang

Frausto

Chung

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…SLC4A11 resides in the basolateral membrane of corneal endothelial cells, facing the corneal stroma (44). About 60 point mutants of SLC4A11 have been reported to date (1,3,12,14,18,20,22,23,34,35,38,40,46,47). Most characterized SLC4A11 mutant proteins display the intracellular retention phenotype characteristic of misfolded membrane proteins.…”

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Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies

Loganathan

Schneider

Morgan

et al. 2016

American Journal of Physiology-Cell Physiology

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SLC4A11, a member of the SLC4 family of bicarbonate transporters, is a widely expressed integral membrane protein, abundant in kidney and cornea. Mutations of SLC4A11 cause some cases of the blinding corneal dystrophies, congenital hereditary endothelial dystrophy, and Fuchs endothelial corneal dystrophy. These diseases are marked by fluid accumulation in the corneal stroma, secondary to defective fluid reabsorption by the corneal endothelium. The role of SLC4A11 in these corneal dystrophies is not firmly established, as SLC4A11 function remains unclear. To clarify the normal function(s) of SLC4A11, we characterized the protein following expression in the simple, low-background expression system Xenopus laevis oocytes. Since plant and fungal SLC4A11 orthologs transport borate, we measured cell swelling associated with accumulation of solute borate. The plant water/borate transporter NIP5;1 manifested borate transport, whereas human SLC4A11 did not. SLC4A11 supported osmotically driven water accumulation that was electroneutral and Na independent. Studies in oocytes and HEK293 cells could not detect Na-coupled HCO transport or Cl/HCO exchange by SLC4A11. SLC4A11 mediated electroneutral NH transport in oocytes. Voltage-dependent OH or H movement was not measurable in SLC4A11-expressing oocytes, but SLC4A11-expressing HEK293 cells manifested low-level cytosolic acidification at baseline. In mammalian cells, but not oocytes, OH/H conductance may arise when SLC4A11 activates another protein or itself is activated by another protein. These data argue against a role of human SLC4A11 in bicarbonate or borate transport. This work provides additional support for water and ammonia transport by SLC4A11. When expressed in oocytes, SLC4A11 transported NH, not NH/H.

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“…Of the ϳ60 SLC4A11 point mutations that have been identified (1,2,11,16,21,24,26,27,35,37,41,42,47,48), 19 are located in the CD and the rest in the MD. Mutations are distributed, with no distinguishable pattern, throughout the protein (Fig.…”

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The cytoplasmic domain is essential for transport function of the integral membrane transport protein SLC4A11

Loganathan

Lukowski

Casey

2016

American Journal of Physiology-Cell Physiology

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Large cytoplasmic domains (CD) are a common feature among integral membrane proteins. In virtually all cases, these CD have a function (e.g., binding cytoskeleton or regulatory factors) separate from that of the membrane domain (MD). Strong associations between CD and MD are rare. Here we studied SLC4A11, a membrane transport protein of corneal endothelial cells, the mutations of which cause genetic corneal blindness. SLC4A11 has a 41-kDa CD and a 57-kDa integral MD. One disease-causing mutation in the CD, R125H, manifests a catalytic defect, suggesting a role of the CD in transport function. Expressed in HEK-293 cells without the CD, MD-SLC4A11 is retained in the endoplasmic reticulum, indicating a folding defect. Replacement of CD-SLC4A11 with green fluorescent protein did not rescue MD-SLC4A11, suggesting some specific role of CD-SLC4A11. Homology modeling revealed that the structure of CD-SLC4A11 is similar to that of the Cl(-)/HCO3(-) exchange protein AE1 (SLC4A1) CD. Fusion to CD-AE1 partially rescued MD-SLC4A11 to the cell surface, suggesting that the structure of CD-AE1 is similar to that of CD-SLC4A11. The CD-AE1-MD-SLC4a11 chimera, however, had no functional activity. We conclude that CD-SLC4A11 has an indispensable role in the transport function of SLC4A11. CD-SLC4A11 forms insoluble precipitates when expressed in bacteria, suggesting that the domain cannot fold properly when expressed alone. Consistent with a strong association between CD-SLC4A11 and MD-SLC4A11, these domains specifically associate when coexpressed in HEK-293 cells. We conclude that SLC4A11 is a rare integral membrane protein in which the CD has strong associations with the integral MD, which contributes to membrane transport function.

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Missense mutation in SLC4A11 in two Pakistani families affected with congenital hereditary endothelial dystrophy (CHED2)

Abstract: This study reports a newly identified mutation (c.2024A>C) in the SLC4A11 gene segregating with the diseased haplotype in two consanguineous Pakistani families.

Cited by 15 publications

References 12 publications

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

Energy Shortage in Human and Mouse Models ofSLC4A11-Associated Corneal Endothelial Dystrophies

Functional assessment of SLC4A11, an integral membrane protein mutated in corneal dystrophies

The cytoplasmic domain is essential for transport function of the integral membrane transport protein SLC4A11

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