Renal tubular homeostasis in health and disease
My group's work lies in the area of renal tubular function and its associated diseases, many of which are inherited and most of which are rare but confer a major health burden on both patients and providers.
Our laboratory research has recently been focused on three areas: the molecular physiology and genetics of the human distal nephron, particularly as it relates to acid-base homeostasis; molecular mechanisms associated with Uromodulin nephropathy; characterization of the human urinary exosome as potential functional player (the first being maintenance of urinary sterility) and source of biomarkers.
Acid-base homeostasis is fine-tuned by highly polarized intercalated cells in the collecting duct of the nephron, where multi-subunit proton pumps on the luminal surface function in tandem with the basolateral anion exchanger AE1. Genes encoding these proteins are mutated in inherited distal RTA. Our studies have identified various determinants of AE1's basolateral residency that are seated in the protein's C-terminal tail, and involve interactions with GAPDH and the sodium pump. We have shown in human and murine studies that some subunits of the specialised type of proton pump have extra-renal sites of action including the inner ear and the nasal mucosa, where they contribute to normal hearing and sense of smell.
Molecular studies currently focus on finding novel regulatory partners for AE1, on regulation of the proton pump via phosphorylation, and on further characterization of human urinary exosomes.
Our laboratory work is complemented by clinic-based studies emanating from the Cambridge Renal Genetic and Tubular Disorders service that I lead, where patients with a variety of such disorders are investigated and managed. Current clinical studies focus upon patient cohorts with Polycystic Kidney Disease, Gitelman Syndrome and recurrent renal stone disease including distal Renal Tubular Acidosis.
E.E. Norgett, A. Yii, K.G. Blake-Palmer, L. Allen, A. Kariminejad, M. Sharifian, A. Najafi & F.E. Karet Frankl. A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3 causing distal Renal Tubular Acidosis. BMC Med Genet, 16:38. doi: 10.1186/s12881-015-0182-12015 (2015).
A.P. Stewart, R.N. Sandford, F.E. Karet Frankl & J.M. Edwardson. Pathogenic uromodulin mutations result in premature intracellular polymerization. FEBS Lett. 89, 89-93 (2015).
Y. Su, R.S. Al-Lamki, K.G. Blake-Palmer, A. Best, A. Zhou & F.E. Karet Frankl. Physical and functional links between kidney anion exchanger 1 and the sodium pump J. Am. Soc. Nephrol. 6, 400-9 (2015).
T.F. Hiemstra, P.D. Charles, T. Gracia, S.S. Hester, L. Gatto, R. Al-Lamki, R.A. Floto, Y. Su, J.N. Skepper, K.S. Lilley & F.E. Karet Frankl. Human urinary exosomes as innate immune effectors. J. Am. Soc. Nephrol. 25, 2017-27 (2014).
M.R. Berry, C. Robinson & F.E. Karet Frankl. Unexpected clinical sequelae of Gitelman Syndrome: Hypertension in adulthood is common and females have higher potassium requirement. Nephrol Dial Transplant 28, 1533-1542 (2013).
E.E. Norgett*, Z.J. Golder*, B. Lorente-Canocas, N. Ingham, K.P. Steel & F.E. Karet Frankl An Atp6v0a4 knockout mouse is a model of distal Renal Tubular Acidosis with hearing loss, with additional extra-renal phenotype. Proc Natl Acad Sci U S A 109, 13775-13780 (2012). *joint first author
A.C. Fry, Y. Su, V. Yiu, A.W. Cuthbert, H. Trachtman & F.E. Karet Frankl. Mutation conferring apical targeting motif on AE1 exchanger causes distal renal tubular acidosis. J Am Soc Nephrol 23, 1238-1249 (2012).
C.M. Taylor & F.E. Karet Frankl. Developing a strategy for the management of rare diseases. Br. Med. J. 344, e2417 (2012).
G.D. Smith, C. Robinson, A.P. Stewart, E.L. Edwards, H.I. Karet, A.G. Norden, R.N. Sandford & F.E. Karet Frankl. Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure. Clin J Am Soc Nephrol. 6, 2766-74 (2011).
Y. Su, K.G. Blake-Palmer, A. Best, A.C.N. Brown, S. Horita, A.C. Fry, A. Zhou, A.N. Smith, A.M. Toye & F.E. Karet. Glyceraldehyde 3-phosphate dehydrogenase is required for band 3 (anion exchanger 1) membrane residency in the mammalian kidney. Am. J. Physiol. 300, F157-66 (2011).
A.N. Smith, R.W. Francis, S. Sorrell & F.E. Karet. The d subunit plays a central role in human vacuolar H+-ATPases J Bioenerg. Biomembr. 40, 371-80 (2008).
Y. Su, K.G. Blake-Palmer, S. Sorrell, B. Javid, K. Bowers, A. Zhou, S.H. Chang, S. Qamar & F.E. Karet. Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1. Am J. Physiol 295, F950-958 (2008).
M.A.J. Devonald, A.N. Smith, J.P. Poon, G. Ihrke & F.E. Karet. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nature Genetics 33, 125-128 (2003).
A.N. Smith, J. Skaug, K.A. Choate, A. Nayir, A. Bakkaloglu, S. Ozen, S.A. Hulton, S.A. Sanjad, E.A Al-Sabban, R.P. Lifton, S.W. Scherer & F.E. Karet. Mutations in ATP6N1B , encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nature Genetics 26, 71-75 (2000).