New genes and treatments for inherited renal disease

• 
  Project Lead
  Prof Judy Savige

  jasavige@unimelb.edu.au

  View researcher's webpage

  +61 3 8344 3260

Project Details

Our work focuses on inherited renal disease. We identified the genes for the commonest inherited kidney disease, Thin basement membrane nephropathy (COL4A3 and COL4A4), and demonstrated that this condition represented the carrier state of autosomal recessive Alport syndrome.

We look for new genes in families with interesting but undiagnosed renal diseases.  Currently, we are examining several families with IgA glomerulonephritis for the mutant genes responsible for this condition.

In addition, we curate databases for Alport syndrome which is the second commonest cause of inherited renal failure after polycystic kidney disease. Laboratories from around the world submit their mutations to us, and we produce genotype-phenotype reviews as more mutations become known.

We study cell lines made from patients with inherited renal disease to understand how the underlying mutations cause disease, and we test out new treatments in these cell lines to try to modify the effect of mutations. We have used gene editing with CRISPR in these cell lines, and have made stem cells with our collaborators to determine whether this form of treatment may be useful in treatment of the inherited human kidney disease.

Finally, we look at the eye abnormalities in inherited renal disease (which occur because of shared structural and developmental features), and what they tell us about disease pathogenesis. We also examine small blood vessels in the retinal photographs to assess blood pressure control since hypertension is common in many renal diseases.

We have PhD and B Sc Honours projects currently investigating new genes for inherited renal disease, and MD students examining the retinal abnormalities in these conditions.

Researchers

• Prof Judy Savige, Director of the Centre for Inherited Renal Disease, physician and researcher
• A/Prof Deb Colville, Dep Director, ophthalmologist and researcher
• Dr Dongmao Wang, post-doctoral scientist
• Jianan Wang, M Bioinformatics student
• Joel Gibson, B Biomed Hons student
• Deb Chang, B Sc Hons student
• Philip Harraka, B Biomed Hons student
• Kieran Sandhu, B Sc Hons student

Collaborators

• Andrew Lonie, Danny Park, Khalid Mahmood, Gayle Philip, Melbourne IBioinformatics, Vctorian Life Sciences Computational Initiativee
• Sharon Ricardo, Monash Biomedicine Discovery Institute
• Andrew Symons and Heather Mack, MH Department of Ophthalmology
• William Vangaal, Director of Cardiology, Northern Health
• David Barit, Director of Nephrology, Northern Health

Funding

• US Alport Foundation
• Kidney Foundation of Canada
• Australian Alport Foundation
• AIRG, France

Research Outcomes

• Dongmao Wang, Mardhiah  Mohammad, Yanyan Wang, Rachel Tan, Lydia S Murray, Sharon Ricardo, Hayat Dagher, Tom van Agtmael, Judy Savige. The chemical chaperone, PBA, reduces ER stress caused by missense mutations in males with X-linked Alport syndrome and potentially slows slow renal failure progression. KI reports 2017;2: 739-748

Research Publications

• J D Parkin… Judy Savige. Interactome of the type III collagen fibril reveals a "flexi-rod” structure comprising flexible sequences interspersed with rigid bioactive domains including two with a hemostatic role. PLoS One. 2017 Jul 13;12(7):e0175582. doi: 10.1371/journal.pone.0175582. eCollection 2017
• Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S. Finlay M, Flinter F. Alport syndrome in women and girls. Clin JASN 2016; 11: 1713-20.
• Judy Savige…Mato Nagel. Alport mutations: variant features that indicate pathogenicity, and further genotype-phenotype correlations. PLoS One. 2016 Sep 14;11(9):e0161802. doi: 10.1371/journal.pone.0161802. eCollection 2016.PMID: 27627812
• Savige J, Sheth S, Leys A, Nicholson A, Mack HG, Colville D. Ocular features in Alport syndrome: pathogenesis and clinical significance. C JASN 2015: 10: 703-9.
• Savige J, Dagher H, Povey S. Mutation databases for inherited renal disease: are they complete, accurate, clinically relevant and freely available? Hum Mutation 2014; 35: 791-3.
• Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and TBMN. JASN 2013; 24: 364-75.
• Storey H, Savige J, Sivakumar V, Flinter FA. Clinical and molecular features in 40 unrelated individuals with autosomal recessive Alport syndrome. JASN 2013: 24: 1945-54.
• Savige J, Ratnaike S, Colville D. Retinal abnormalities in inherited renal disease. JASN 2011; 22: 1403-15.
• Ooi QL, Newk-Fon Hey Tow FK, Deva R, Alias MA, Kawasaki R, Wong TY, Mohamad N, Colville D, Hutchinson A, Savige J. Narrowing of the microvasculature in chronic kidney disease depends on the severity of renal impairment. Clin JASN 2011; 6: 1872-8.
• Parkin JD, San Antonio JD, Pedchenko V, Hudson B, Jensen ST, Savige J. Mapping structural landmarks and mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions and variation in phenotypes in inherited diseases affecting basement membranes. Human Mutation 2010; 31: 1179-84