Autosomal dominant Alport syndrome due to a COL4A4 mutation with an additional ESPN variant detected by whole-exome analysis
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Alport syndrome (AS) is a rare hereditary disease that presents with chronic kidney disease and sensorineural hearing loss, and is diagnosed by its clinical features, pathological features on renal tissue, and mode of inheritance. We report a woman in her 20 s who exhibited persistent haematuria with normal renal function and sensorineural hearing loss. Her family members exhibited the same clinical findings among three generations and were suspected of having autosomal dominant AS (ADAS). Renal biopsy showed minor glomerular abnormalities on light microscopy and extensive thinning of the glomerular basement membrane on electron microscopy. Whole-exome analysis revealed a known COL4A4 (type IV collagen α4) mutation (c. 2510 G > C: p. Gly837Ala). Two pedigrees with the same variant have been reported previously, one as ADAS and the other as autosomal recessive AS. However, these two cases exhibited no sensorineural hearing loss. The analysis in the present case revealed another missense variant in ESPN (Espin), an actin-bundling protein, which is a causative gene for sensorineural hearing loss. Although the pathophysiological significance of this novel missense variant needs to be clarified, computational analysis predicted that the variant creates a new phosphorylation site for protein kinase C. Our case suggests a possible association of hereditary sensorineural hearing loss with ADAS. Whole-exome analysis should be considered to diagnose hereditary and multiple-organ disorders.
KeywordsAlport syndrome Type IV collagen α4 (COL4A4) Espin (ESPN) Sensorineural hearing loss Whole-exome analysis
Autosomal dominant Alport syndrome
Autosomal recessive Alport syndrome
X-linked Alport syndrome
We thank the patient and her family for taking part in this study.
YI designed and YI, YM, and YA organized the study. YI and TM cared for the patient. TN, MN, and YK performed renal biopsy and prepared the samples. YK provided pathological diagnoses. KS, NM, and NM performed whole-exome analysis and Sanger sequencing. YI and KS performed computational analysis. YI, AH, RM, YN, and MM reviewed the literature and interpreted the data obtained from all procedures. YI and MM wrote the manuscript, which was edited by all other authors. All authors have read and approved the manuscript.
This research received no specific grant from any funding agency.
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interest exists.
All procedures performed in the studies were in accordance with the Ethical Committee of Kumamoto University Graduate School of Medical Sciences.
Consent for publication
The patients provided written informed consent to participate in this study. The patients provided written informed consent to publish this case report, including case description, medical data, and images, maintaining anonymity.