The human genome project: Implications for hypertension

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Our approach consisted in the isotalion of a strain of rats with andh its control normotensive strain genetic hypertension ( (MNS). Using classical Senetic crosses coupled to physiological, biochemical and molecular studies, a ,poim mutation within the cytoskeletal protein ‘adduci., has heen identified m a cause of a consistent portion of hypertension in !hese animals. Rat epithelial adduci” hfHS cDNA showed a sis”ificmt cell (ransfccted imxeme in N.-K pump activity at Vmax and N.-K pump units o. the cell surface. compared with cells tmmfccted with MNS cDNA, These findi.ss may explain the faster Na.K pump activity and tubular reabsorption in MHS kidney with their greater prr,ssor effect after transplantation m compsrcd to MNS kidneys, [n view of the many pathophy8iolegical similarities between these rau and a subset of humans with primary hypertension and the very high amin.mcid homology between the adducin8 of the IWO specie’, studies were alm conducted in ma”. Case-control and sib-pair studies in independent populations. using eilher DNA markers wmo”ndins the add.cin locus or mutations within the add”ci” coding region, showed data consistent with a role of this protein t also in human hypertension. Moreover, compared 10 palients with the wild allele. patients carrying the ‘mulated< hypertensive allele display alteration in the relationship between body sodium and blood pressure. In these patiem% lhc pressure-natriuresit curve after scdium i“f.sion is less steep and the fall in blood prewure wilh diuretics is greater than in patients with wild type adducim Three data am. consistent with a role of add.cin i“ renal N. handling as previously shown in the rat genetic model. Tbereforc, to our knowledge, this is an unique condition where spommeous mula[ion occurring on the 8amo gene may cause hypertension through modification in renal Na handling in two specie$ Ihal diverged approximately S0-90 million years ago. 1) PNAS 1994: 91: 3999-4C03: 2) Hypertension 1995: 25: 320.326 3) JCI 19%; 97: 2S15.2S22 4) The Lmcet 1997: 349: 1353-1357: S) The Lancet 1997: 350: 369 6) Kidney Intern 1998; iLIUESS

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Chair ./ Nephrolo.gy, Milan University, S. Raffaele Hospiml, Milm ,,.,., n the role m ofj sodium in the d oh eb r a m W i e factor in a portion of h p the genetic basis of t p still unk”mv”.

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