Endocytic protein reabsorption in the proximal tubule necessitates a sophisticated mechanism since abnormalities can result in tubular proteinuria. The particular processes of endocytosis and receptor and cargo processing remained unknown. EHD1 is a member of a protein family that is thought to be involved in intracellular vesicle scission and ciliogenesis. However, the role of EHD1 in human tissues, particularly the kidney, remained unclear. For a study, researchers sought to discover the disease-causing gene in patients with tubular proteinuria and deafness, genetic approaches were applied. To examine the pathogenesis, diagnostic and functional tests were undertaken on patients and disease models.
About 6 people (5–33 years) with proteinuria and high-frequency hearing impairment were found to have the homozygous missense mutation c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7–2.1 g/d) was mostly composed of low molecular weight proteins, indicating poor renal proximal tubular endocytosis of filtered proteins. A high-frequency hearing loss and defective receptor-mediated endocytosis in proximal tubules were also seen in Ehd1 deletion and Ehd1R398W/R398W knock-in mice, while a zebrafish model demonstrated decreased capacity to reabsorb low molecular weight dextran. Surprisingly, ciliogenesis was unaffected in patients. A silicon structural study suggested that the R398W variation will have a destabilizing impact and may interfere with nucleotide binding, resulting in decreased EHD1 oligomerization and membrane remodeling capabilities.
A previously unknown autosomal recessive condition caused by a homozygous missense mutation of EHD1 was characterized by sensorineural deafness and tubular proteinuria. Patients with hearing loss should be tested for recessive EHD1 mutations, especially if tubular proteinuria is present.