A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness

Area of Science:

• Molecular Biology
• Genetics
• Nephrology

Background:

• Protein reabsorption in kidney proximal tubules involves complex machinery; defects cause tubular proteinuria.
• Endocytosis mechanisms and receptor processing are not fully understood.
• EHD1 protein family is implicated in intracellular vesicle scission and ciliogenesis, but its role in human kidney was unknown.

Purpose of the Study:

• To investigate the role of EHD1 in human kidney proximal tubule function.
• To identify the genetic cause of a disorder characterized by tubular proteinuria and deafness.

Main Methods:

• Genetic analysis of patients with tubular proteinuria and deafness.
• Functional studies in patient-derived models and animal models (mice, zebrafish).
• In silico structural analysis of the identified EHD1 variant.

Main Results:

• Six individuals with proteinuria and hearing loss were found to have a homozygous EHD1 missense variant (p.R398W).
• EHD1 variant caused impaired proximal tubule endocytosis in mice and zebrafish, leading to low molecular weight proteinuria and hearing deficits.
• The R398W variant destabilizes EHD1, affecting nucleotide binding, oligomerization, and membrane remodeling, but not ciliogenesis.

Conclusions:

• A homozygous EHD1 variant causes a novel autosomal recessive disorder with sensorineural deafness and tubular proteinuria.
• Consider recessive EHD1 variants in patients with hearing impairment and tubular proteinuria.