Issler, N; (2014) Clinical, genetic and molecular studies into hereditary renal tubular proteinuria. Doctoral thesis , UCL (University College London).

Abstract

BACKGROUND We identified patients from consanguineous families from within a genetic isolate who presented with an unknown combination of renal tubular proteinuria and sensorineural hearing loss. METHODS Patients were carefully characterised concerning kidney function including 99m-Tc-DMSA scan and renal biopsy. We applied multipoint parametric whole-genome linkage analysis and haplotype reconstruction in four families with six affected children. We performed exome capture and next generation sequencing in five affected children. Newly identified mutations in a gene with presumed intracellular trafficking functions were evaluated with the use of different cell models. Protein expression within the kidney and intracellular trafficking were further investigated by immunocytochemical analysis. RESULTS All patients investigated had normal glomerular filtration rate, a pathological 99m-Tc-DMSA renal scan with no tracer uptake and abnormal electron microscopy finding within the microvilli of the proximal tubule. Linkage studies identified a single significant genome-wide locus with a LOD score of 7.2 on chromosome 11. This region of 1.5 million bases, contained a total of 48 annotated genes. Analysing the sequencing results of those genes within this linked region revealed a homozygous missense mutation in the EHD-1 gene in all affected individuals. The mutation segregated in an autosomal recessive fashion within the families and was absent from 196 healthy ethnically matched control alleles. This mutation, when expressed in HeLa and renal proximal tubular LLC-PK1 cells caused significant and specific changes in the endosomal recycling compartment, an intracellular compartment related to processing and recycling of cellular substrates. CONCLUSION We identified a founder mutation in a gene causing a previously unrecognised and undiagnosed rare autosomal recessive Mendelian disorder, showing clinically signs and symptoms of renal tubular low molecular weight proteinuria and hearing deficit. Our findings indicate that this gene plays a major role in renal tubular low molecular protein handling and inner ear function.

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