Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3–COL4A5) and Their Association With Other Kidney Conditions: A Review

Savige, Judy; Harraka, Philip

doi:10.1053/j.ajkd.2021.04.017

Cited by 37 publications

(26 citation statements)

References 87 publications

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“…48,49 IgA glomerulonephritis and heterozygous pathogenic variants occur together too often to be coincidental and the thinned GBM may facilitate glomerular immune complex deposition. 50 Inappropriateness of "AD Alport Syndrome" as a Diagnosis These observations that pathogenic heterozygous COL4A3 or COL4A4 variants are uncommonly associated with ESKF, hearing loss, and ocular abnormalities suggest that the term "AD Alport syndrome" itself is not appropriate since 'syndrome' implies the presence of extra-renal features.…”

Section: Explanation Of the Reduced Risk Of Eskf And Extra-renal Feat...mentioning

confidence: 99%

Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

Savige

2022

Kidney International Reports

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Section: Explanation Of the Reduced Risk Of Eskf And Extra-renal Feat...mentioning

confidence: 99%

Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

Savige

2022

Kidney International Reports

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“…Recently JS and Philip Harrak reported that how often both diseases occur together is unknown because few individuals with IgA glomerulonephritis routinely undergo electron microscopy for GBM thinning or testing for genetic variants. On the other hand, heterozygous COL4A3 and COL4A4 variants and IgA disease each affect ~1% of the population, so the conditions might coexist by chance in 0.01% [ 38 ]. Kohei Omachi (Washington University, St. Louis, USA), from the group of Jeff H. Miner, reported on ways to detect and assess the pathogenicity of novel variants, having established a collagen alpha 345(IV) heterotrimer formation assay that is amenable to high throughput screening by using a split NanoLuc luciferase complementarity system [ 39 ].…”

Section: What To Do When Alport Syndrome Is Strongly Suspected But a ...mentioning

confidence: 99%

The 2019 and 2021 International Workshops on Alport Syndrome

et al. 2022

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In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: COL4A3 , COL4A4 , and COL4A5 encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome.

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“…Although there are isolated reports of complement pathway risk alleles in IgA glomerulonephritis, the only major ones are ITGAM and ITGAX that code for integrins that facilitate complement-dependent phagocyte activation and immune complex clearance. Interestingly both IgA glomerulonephritis and retinal drusen are also associated with variants in COL4A3 or COL4A4 , and GBM thinning that may facilitate IgA movement into the mesangium 43 .…”

Section: Discussionmentioning

confidence: 99%

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis

Harraka

Wightman

Akom

et al. 2022

Sci Rep

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Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls. The cohort comprised 122 individuals with IgA glomerulonephritis including 89 males (73%), 49 individuals (40%) of East Asian or Southern European ancestry, with an overall median age of 54 years (34–64), and median disease duration of 9 years (4–17). Thirty-nine (33%) had an eGFR < 60 ml/min/1.73 m2 and 72 had previously reached kidney failure (61%). Overall mean drusen counts were higher in IgA glomerulonephritis (9 ± 27) than controls (2 ± 7, p < 0.001). Central counts ≥ 10 were also more common (OR = 3.31 (1.42–7.73, p = 0.006), and were associated with longer disease duration (p = 0.03) but not kidney failure (p = 0.31). Larger drusen were associated with more mesangial IgA staining (p = 0.004). Increased drusen counts were also present in IgA glomerulonephritis secondary to Crohn’s disease but not with Henoch-Schonlein purpura. The finding of retinal drusen in IgA glomerulonephritis is consistent with complement activation and represents a model for better understanding glomerular immune deposition and a supporting argument for treatment with anti-complement therapies.

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Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3–COL4A5) and Their Association With Other Kidney Conditions: A Review

Cited by 37 publications

References 87 publications

Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

Heterozygous Pathogenic COL4A3 and COL4A4 Variants (Autosomal Dominant Alport Syndrome) Are Common, and Not Typically Associated With End-Stage Kidney Failure, Hearing Loss, or Ocular Abnormalities

The 2019 and 2021 International Workshops on Alport Syndrome

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis

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