Reassessing the pathogenicity of c.2858G&gt;T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

Zhang, Yanqin; Ding, Jie; Zhang, Hongwen; Zhong, Xing; Liu, Xiaoyu; Xu, Ke; Wang, Fang

doi:10.1038/s41431-019-0523-1

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…21,[32][33][34] However, our recent gene analysis and reports from other groups have indicated that G953V is a single-nucleotide polymorphism variant and is nonpathogenic. 22 Consistent with those views, G953V exhibited the same trimer formation and secretion abilities as the wild type in our cell-based trimerization assay. We note that G953V is the only mutant without a significant difference in both N-and C-terminal trimer assays.…”

Section: G953vsupporting

confidence: 88%

Trimerization and Genotype–Phenotype Correlation of COL4A5 Mutants in Alport Syndrome

Kamura

Yamamura

Omachi

et al. 2020

Kidney International Reports

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Introduction: Alport syndrome is a hereditary glomerulonephritis that results from the disruption of collagen a345(IV) heterotrimerization caused by mutation in COL4A3, COL4A4 or COL4A5 genes. Many clinical studies have elucidated the correlation between genotype and phenotype, but there is still much ambiguity and insufficiency. Here, we focused on the a345(IV) heterotrimerization of a5(IV) missense mutant as a novel factor to further understand the pathophysiology of Alport syndrome. Methods: We selected 9 a5(IV) missense mutants with typical glycine substitutions that clinically differed in disease progression. To quantify the trimerization of each mutant, split nanoluciferase-fused a3/a5 mutants and a4 were transfected into the cells, and intracellular and secreted heterotrimer were detected by luminescence using an assay that we developed previously. Results: Trimer formation and secretion patterns tended to be similar to the wild type in most of the mutations that did not show proteinuria at a young age. On the other hand, trimer secretion was significantly reduced in all the mutations that showed proteinuria and early onset of renal failure. One of these mutants has low ability of intracellular trimer formation, and the others had the defect of low-level secretion. In addition, the mutant that is assumed to be nonpathogenic has similar trimer formation and secretion pattern as wild-type a5(IV). Conclusion: The result of cell-based a345(IV) heterotrimer formation assay was largely correlated with clinical genotype-phenotype. These trimerization assessments provide additional phenotypic considerations and may help to distinguish between pathogenic and nonpathogenic mutations.

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Section: G953vsupporting

confidence: 88%

Trimerization and Genotype–Phenotype Correlation of COL4A5 Mutants in Alport Syndrome

Kamura

Yamamura

Omachi

et al. 2020

Kidney International Reports

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“…The nature of other variants such as NM_000495.5:c.2858G>T (rs78972735; p.(Gly953Val)) in COL4A5 [ 55 ], and NM_000092.5:c.1634G>C (rs1800516; p.(Gly545Ala)) and NM_000092.4(COL4A4):c.2996G>A (rs13027659 p.(Gly999Glu)) in COL4A4 is less clear. All are very abundant in certain ancestries.…”

Section: Modification Of the Acmg/amp Criteria For The Col4a3–col4a5 Genes And Rationalementioning

confidence: 99%

“…All are very abundant in certain ancestries. p.(Gly953Val) is also located immediately adjacent to an interruption in the collagenous domain of the collagen IV α5 chain, but it is not on its own associated with haematuria, kidney failure or GBM lamellation [ 55 ], and has conflicting interpretations of pathogenicity in Clin Var (www.ncbi.nlm.nih.gov/clinvar/variation/24573/). Both p.(Gly545Ala) and p.(Gly999Glu) affect Gly residues within the collagenous domain of the collagen IV α4 chain itself.…”

Section: Modification Of the Acmg/amp Criteria For The Col4a3–col4a5 Genes And Rationalementioning

confidence: 99%

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

et al. 2021

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The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

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“…For example, missense variants that change Gly to another amino acid in COL4A5 are always considered to be pathogenic. However, p.Gly953Val is considered to be nonpathogenic [ 22 ] and p.Gly1000Val leads to a very mild phenotype resembling benign familial hematuria [ 23 ]. We are now attempting to reveal these differences using this approach.…”

Section: Triple Helix Formation Assaymentioning

confidence: 99%

Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome

Nozu

Takaoka

Kai

et al. 2020

Kidney Res Clin Pract

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Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients' induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.

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Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families

Cited by 5 publications

References 26 publications

Trimerization and Genotype–Phenotype Correlation of COL4A5 Mutants in Alport Syndrome

Trimerization and Genotype–Phenotype Correlation of COL4A5 Mutants in Alport Syndrome

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome

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