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.

Reference:jasn.asnjournals.org/content/33/4/732