Dr John Sayer
Academic Clinical Senior Lecturer

  • Email: john.sayer@ncl.ac.uk
  • Telephone: +44 (0) 191 241 8608
  • Fax: +44 (0) 191 241 8666
  • Address: Institute of Genetic Medicine
    Newcastle University
    International Centre for Life
    Central Parkway
    Newcastle upon Tyne
    NE1 3BZ

Roles and Responsibilities:

Honorary Consultant Nephrologist, Newcastle upon Tyne Hospitals NHS Foundation Trust.

 

 

 

 

 

Molecular genetics of the cystic kidney disease Nephronophthisis

A paradigm states that all genes which are mutated in cystic kidney disease express their protein products in the primary cilia/basal body/centrosome. This implicates the primary cilium and its signalling pathways in the pathophysiology of kidney cyst formation.

Nephronophthisis, which literally means a wasting away of nephrons, is an autosomal recessive cystic kidney disease, which leads to end-stage renal failure within the first three decades of life. Originally described in 1951, its pathophysiology remained a mystery for over 45 years. Linkage studies have now identified several genes involved in nephronophthisis, most recently NPHP6 and AHI1, genes mutated in nephronophthisis associated with retinal degeneration and cerebellar vermis aplasia (Joubert syndrome). The “nephrocystin” proteins all colocalise to renal cilia or centrosome. Despite numerous genetic discoveries however, the mechanisms of disease remain unsolved. A role for nephrocystin proteins may also exist at cell-cell junctions and focal adhesion complexes, perhaps in maintaining planar cell polarity.

A potential clue is that all cystic kidney diseases present with decreased urinary concentration ability and that vasopressin V2 receptor antagonists have been successfully used in some rodent models of cystic kidney disease. In order to understand these processes further we are exploring models of disease to mimic the disease in kidney. These include functional epithelial cell models, developmental models involving Danio rerio and murine knockout models. Funding for these experiments has been generously provided by GlaxoSmithKline, as part of a Clinician Scientist fellowship to Dr. Sayer, the MRC, Kids Kidney Reseach, Northern Counties Kidney Research Fund and Kidney Research UK.