Scientists from the University of Leeds have discovered the mechanisms of a protein known to play an active part in the inherited kidney disorder, Dent's disease. The findings provide a new focus for future therapies for the disease, for which there is currently no cure.
Dent's disease is an extremely rare illness caused by a genetic mutation on the X chromosome. Affecting mostly men, its main symptom is kidney stones often followed by a deterioration of kidney function and in many cases chronic kidney failure. Treatment for the disease is focused on alleviating symptoms and can involve kidney transplant.
Scientists from the University's Faculty of Biological Sciences have uncovered the role of a transporter protein, called CLC-5, which is known to be faulty in many sufferers of Dent's disease.
Lead researcher Dr Jonathan Lippiat says, "This is a rare genetic disease so it's impossible to know the exact number of sufferers worldwide. Dent's disease could be the underlying cause of kidney stones or kidney failure for a larger number of people and it could be that a number of Dent's sufferers go undiagnosed. The faulty gene itself has been known about for quite a while, but there's been no concrete evidence about the function it fulfils. That's why we're excited by these findings - they provide us with a whole new area to examine in the search for therapies for Dent's disease."
In a research project supported by the Wellcome Trust, Dr Lippiat and his team have discovered that CLC-5 facilitates a crucial function by allowing certain ions to pass through cell membranes so they can reach the places they are needed.
The kidneys filter our blood, removing waste, but minerals and hormones that we need to remain healthy need to be reabsorbed. In order for the cells in the kidney to reabsorb effectively, a process called endocytosis takes place to allow larger molecules to travel through the cell membrane.
In endocytosis, a compartment is created in the cell membrane for the molecule to enter. This compartment - or endosome - needs to be acidic in order for the process to work effectively. The research findings show that CLC-5 delivers protons into endosomes, which causes acidification to occur, so when it CLC-5 is faulty, endocytosis cannot take place effectively.
"If endocytosis can't take place we lose vital vitamins and hormones," says Dr Lippiat. "CLC-5 is actually part of a family of proteins, some of which are implicated in other diseases, so these findings could have important consequences when we're looking at the role of other proteins in the same family."
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Jennifer Tomlinson, Royal Society-Research Fellows Enhancement Award (Dec 2017), £94,681
Helen Miller, AB AGri Grant (Dec 2017), £73,600
Simon Walker, Royal Society Enhancement Award (Dec 2017), £10,000
Carrie Ferguson, Bryan Taylor, Harry Rossiter, The Physiological Society (Dec 2017), £7,392
Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
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Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
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Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000
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Stefan Kepinski, Yoselin Benitez-Alfonso, Tom Bennett, Michelle Peckham, BBSRC (Jun 2017), £331,000
Roman Tuma, Lars Jeuken, Paul Millner, Sheena Radford, Peter Stockley and MAPS/FMH, BBSRC (Jun 2017), £222,000
Vas Ponnambalam, Darren Tomlinson, Stephen Wheatcroft, BHF (May 2017), £107,878
Graham Askew in collaboration with Bangor University, BBSRC (Mar 2017), £477,383
Stephen Muench, BBSRC (Mar 2017), £132,945
Nic Stonehouse, MRC (Mar 2017), £906,341
Bill Kunin, Steve Sait, BBSRC (Mar 2017), £602,831
Adrian Goldman, EU (Mar 2017), £546,576
Sheena Radford, Wellcome Trust (Mar 2017), £1,836,482
Beatrice Filippi, Royal Society (Mar 2017), £15,000
Tom Bennett, Royal Society (Mar 2017), £15,000
Jamie Johnston, Royal Society (Mar 2017), £15,000
Ryan Seipke, BBSRC (Feb 2017), £52,116
Mary O'Connell, BBSRC (Feb 2017), £46,986
Hannah Dugdale, NERC (Feb 2017), £504,138
Anastasia Zhuravleva, EPSRC (Jan 2017), £100,792