Alport syndrome: facts and opinions

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Abstract

In this commentary, I review recent advances in Alport syndrome genetics, diagnostics, and therapeutics. I also offer some opinions regarding strategies to optimize the early identification of affected individuals to promote early therapeutic intervention.

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Most cited references 48

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Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.

Ivan Gomez, Deidre MacKenna, Bryce Johnson … (2015)

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy.

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Genotype-phenotype correlation in X-linked Alport syndrome.

Mir Reza Bekheirnia, Berenice Reed, Martin C Gregory … (2010)

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5' end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3' end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5; end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.

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X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.

J Hertz, Willem M de Vos, M. Sanak … (2000)

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

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Author and article information

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000Research (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 17 January 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: 50

Affiliations

[1 ]Department of Pediatrics, Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis, MN, USA

Author notes

[a ] kasht001@ 123456umn.edu

Competing interests: The Alport Syndrome Treatments and Outcomes Registry (ASTOR, alportregistry.org), of which the author is Executive Director, is supported by the Alport Syndrome Foundation, the Kenneth and Claudia Silverman Family Foundation, and the Schuman and Pedersen families and participates in the Athena Study sponsored by Regulus Therapeutics (Clinicaltrials.gov identifier NCT02136862). The author has served as a consultant to Regulus Therapeutics and Roche. ASTOR has also received research support from NIDDK and the Novartis Institute for Biomedical Research.

Article

DOI: 10.12688/f1000research.9636.1

PMC ID: 5247785

PubMed ID: 28163907

SO-VID: 671a19be-0eca-4e18-ad82-3ca782dd3e63

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 13 January 2017

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