A review of clinical characteristics and genetic backgrounds in Alport syndrome

Nozu, Kandai; Nakanishi, Koichi; Abe, Yoshifusa; Udagawa, Tomohiro; Okada, Shinichi; Okamoto, Takayuki; Kono, Hiroshi; Kanemoto, Katsuyoshi; Kobayashi, Anna; Tanaka, Eriko; Tanaka, Kazuki; Hama, Taketsugu; Fujimaru, Rika; Miwa, Saori; Yamamura, Takehira; Yamamura, Natsusmi; Horinouchi, Tomoko; Minamikawa, Shogo; Nagata, Michio; Iijima, Kazumoto

doi:10.1007/s10157-018-1629-4

Cited by 170 publications

(189 citation statements)

References 47 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…The diagnosis of patients with heterozygous mutations in COL4A3 or COL4A4 is controversial [7,[13][14][15][16][17]35], resulting in confusion among nephrologists. This is primarily because the phenotype of heterozygous COL4A3 or COL4A4 variants varies from no urinary abnormality, to isolated hematuria, to ESRD.…”

Section: Discussion Regarding the Diagnosis Of Heterozygous Col4a3 Ormentioning

confidence: 99%

How to resolve confusion in the clinical setting for the diagnosis of heterozygous COL4A3 or COL4A4 gene variants? Discussion and suggestions from nephrologists

et al. 2020

Self Cite

View full text Add to dashboard Cite

Both thin basement membrane nephropathy (TBMN) and autosomal dominant Alport syndrome (ADAS) are types of hereditary nephritis resulting from heterozygous mutations in COL4A3 or COL4A4 genes. Although TBMN is characterized by hematuria and thinning of the glomerular basement membrane (GBM) with excellent renal prognosis, some patients develop end-stage renal disease (ESRD) later in life. In contrast, although AS is characterized by progressive nephropathy with lamellation of the GBM, there are some patients diagnosed with ADAS from a family history of ESRD but who only suffer from hematuria with GBM thinning. These findings indicate a limitation in distinction between TBMN and ADAS. Diagnosis of AS is significant because it facilitates careful follow-up and early treatment, whereas diagnosis of TBMN can underestimate the risk of ESRD. However, some experts are against using the term ADAS as the phenotypes of heterozygous variants vary from no urinary abnormality to ESRD, even between family members with the same mutations, indicating that unknown secondary factors may play a large role in the disease severity. These diagnostic difficulties result in significant confusion in clinical settings. Moreover, recent studies revealed that the number of patients with chronic kidney disease caused by these gene mutations is far higher than previously thought. The aim of this article is to review differing opinions regarding the diagnosis of heterozygous COL4A3 or COL4A4 variants, and to highlight the importance for nephrologists to recognize this disease, and the importance of the need to reclassify this disease to minimize the current confusion.

show abstract

Section: Discussion Regarding the Diagnosis Of Heterozygous Col4a3 Ormentioning

confidence: 99%

How to resolve confusion in the clinical setting for the diagnosis of heterozygous COL4A3 or COL4A4 gene variants? Discussion and suggestions from nephrologists

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…7 In AS, the assembly of the collagen triple helix is impaired and more susceptible to proteolytic processes. [8][9][10] The main site of pathology is the kidney because of the high amount of collagen IV in the glomerular basement membrane. As a result of the respective mutations in AS, the glomerular basement membraneas a main contributor for the glomerular filtration barrieris lamellated.…”

mentioning

confidence: 99%

Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome

Hess

Pfau

Wintergerst

et al. 2020

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

spectrum of the foveal configuration and foveal avascular zone in patients with Alport syndrome. Invest Ophthalmol Vis Sci. 2020;61(2):5. https://doi.org/10.1167/iovs.61.2.5 PURPOSE.To investigate characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. METHODS.Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1°and 3°were correlated. RESULTS.Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = −0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.007), in line with OCT findings of a staircase foveopathy. CONCLUSIONS.The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation.

show abstract

“…A strong correlation has been found between the COL4A5 mutation type and the age developing end-stage renal disease in male patients Nozu et al, 2019). It has been reported previously that phenotypic differences in COL4A5 carriers can attribute to X chromosome inactivation (Shimizu et al, 2006;Wang et al, 2007;Rheault, 2012;Allred et al, 2015).…”

Section: Discussionmentioning

confidence: 83%

Endoplasmic Reticulum Stress Activation in Alport Syndrome Varies Between Genotype and Cell Type

Liang

Xing

et al. 2020

Front. Genet.

View full text Add to dashboard Cite

Alport syndrome is a hereditary progressive chronic kidney disease caused by mutations in type IV collagen genes COL4A3/4/5. X-linked Alport syndrome (XLAS) is caused by mutations in the COL4A5 gene and is the most common form of Alport syndrome. A strong correlation between the type of COL4A5 mutation and the age developing endstage renal disease in male patients has been found. Mutation to the a (IV) chain causes retention of the protein to the endoplasmic reticulum lumen, which causes endoplasmic reticulum stress (ERS) and subsequent exertion of deleterious intracellular effects through the activation of ERS. The exact time point that mutant type IV collagen a chain exerts its deleterious effects remains elusive. In this study, we explored the relationship between the COL4A5 genotype and cell type in ERS activation. We obtained skin fibroblasts from Alport syndrome patients with different COL4A5 mutation categories [i.e., a missense mutation (c.4298G > T, p.Gly1433Val) in exon 47, a splicing mutation (c.1949-1G > A) in intron 25 and an insertion (c.573_c.574insG, p. Pro193Alafs*23) in exon 10], and then reprogrammed these fibroblasts into induced pluripotent stem cells (iPSCs). Interestingly, no significant dysregulation of ERS pathway markers was observed for the three COL4A5 mutant iPSCs; however, significant activation of ERS in COL4A5 mutant fibroblasts was observed. In addition, we found that the activation levels of some ERS markers in fibroblasts varied among the three COL4A5 mutation types. Mutant COL4A5 proteins were demonstrated to have different effects on cells at different stages of ontogenesis, providing a theoretical basis for choosing the timing of intervention. The observed differences in activation of ERS by the COL4A5 mutant fibroblasts may contribute to the intracellular molecular mechanisms that describe the correlation between genotype and clinical features in XLAS.

show abstract

A review of clinical characteristics and genetic backgrounds in Alport syndrome

Cited by 170 publications

References 47 publications

How to resolve confusion in the clinical setting for the diagnosis of heterozygous COL4A3 or COL4A4 gene variants? Discussion and suggestions from nephrologists

How to resolve confusion in the clinical setting for the diagnosis of heterozygous COL4A3 or COL4A4 gene variants? Discussion and suggestions from nephrologists

Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome

Endoplasmic Reticulum Stress Activation in Alport Syndrome Varies Between Genotype and Cell Type

Contact Info

Product

Resources

About