Corneal endothelial cell abnormalities in X-linked Alport syndrome

Nicklason, Eleanor; Mack, Heather G; Beltz, Jacqueline; Jacob, Julie A.; Farahani, Mina; Colville, Deb; Savige, Judy

doi:10.1080/13816810.2019.1709126

Cited by 13 publications

(10 citation statements)

References 40 publications

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“…38,39 This epithelial cell loss is not confined to the kidney, but also explains the extrarenal manifestations in the cornea and retina. 40 A canine model of Alport syndrome also suggests that a reduced nephron number at birth results in focal and segmental glomerulosclerosis from hyperfiltration. 41 However genotype still did not correlate with age at kidney failure in women and girls with X-linked Alport syndrome despite correlations between genotype and age at proteinuria, and between age at proteinuria and kidney failure onset.…”

Section: Discussionmentioning

confidence: 99%

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A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

Gibson¹,

Gooyer²,

Huang³

et al. 2022

Kidney International Reports

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Section: Discussionmentioning

confidence: 99%

“… 38 , 39 The epithelial loss is not confined to the kidney, but also explains the extrarenal manifestations in the cornea and retina. 40 In addition, a canine model of Alport syndrome suggests that a reduced nephron number at birth contributes to secondary focal and segmental glomerulosclerosis from hyperfiltration. 41 …”

Section: Discussionmentioning

confidence: 99%

A Systematic Review of Pathogenic COL4A5 Variants and Proteinuria in Women and Girls With X-linked Alport Syndrome

Gibson¹,

Gooyer²,

Huang³

et al. 2022

Kidney International Reports

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“…In contrast, the α chains resulting from a missense variant are often associated with a disrupted trimer that is retained within the podocyte ER (11,12), increasing ER stress and podocyte loss (13,14). Of all the missense variants, the majority (30%) are Gly substitutions in the intermediate collagenous domain.…”

Section: Structure Of the Collagen IV Networkmentioning

confidence: 99%

Genotype-Phenotype Correlations for Pathogenic COL4A3–COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome

et al. 2022

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Alport syndrome is inherited as an X-linked (XL), autosomal recessive (AR), or autosomal dominant (AD) disease, where pathogenic COL4A3 – COL4A5 variants affect the basement membrane collagen IV α3α4α5 network. About 50% of pathogenic variants in each gene (major rearrangements and large deletions in 15%, truncating variants in 20%, splicing changes in 15%) are associated with “severe” disease with earlier onset kidney failure, and hearing loss and ocular abnormalities in males with XL inheritance and in males and females with AR disease. Severe variants are also associated with early proteinuria which is itself a risk factor for kidney failure. The other half of pathogenic variants are missense changes which are mainly Gly substitutions. These are generally associated with later onset kidney failure, hearing loss, and less often with major ocular abnormalities. Further determinants of severity for missense variants for XL disease in males, and in AD disease, include Gly versus non-Gly substitutions; increased distance from a non-collagenous interruption or terminus; and Gly substitutions with a more (Arg, Glu, Asp, Val, and Trp) or less disruptive (Ala, Ser, and Cys) residue. Understanding genotype-phenotype correlations in Alport syndrome is important because they help predict the likely age at kidney failure, and the need for early and aggressive management with renin-angiotensin system blockade and other therapies. Genotype-phenotype correlations also help standardize patients with Alport syndrome undergoing trials of clinical treatment. It is unclear whether severe variants predispose more often to kidney cysts or coincidental IgA glomerulonephritis which are recognized increasingly in COL4A3-, COL4A4 - and COL4A5-associated disease.

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“…FSGS probably occurs with pathogenic COL4A3 -COL4A5 variants because the abnormal glomerular basement membrane (GBM) results in loss of the overlying podocytes 5 and secondary glomerular hyperfiltration. Similar changes also occur in the cornea 6 and presumably in the retina where the temporal retina is thinned overlying Bruch's membrane 7 . Pathogenic variants in the genes affected in Alport syndrome are the commonest variants found in cohorts with FSGS 4 .…”

Section: Introductionmentioning

confidence: 71%