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Rapid Diagnosis and Identification of Cross-Over Sites in Patients with Glucocorticoid Remediable Aldosteronism

Department of Medical Genetics (A.A.M., K.F.K., A.M., S.L., L.J.G., N.E.H.), Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom; and Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics (G.C.I., A.J., J.M.C.C.), Western Infirmary, Glasgow G11 6NT, Scotland, United Kingdom

Address all correspondence and requests for reprints to: A. MacConnachie, Department of Medical Genetics, University Medical Buildings, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant cause of primary aldosteronism and high blood pressure resulting from a chimeric 11ß-hydroxylase/aldosterone synthase gene. Abnormal expression of aldosterone synthase causes primary aldosteronism, which can be inhibited by glucocorticoids. Diagnosis of GRA has depended on the identification of a restriction enzyme product in genomic DNA of affected individuals. Recently, a two-tube long PCR method was described that allowed diagnosis of GRA in a kindred in Australia. A similar long PCR method confirmed the diagnosis of GRA in members of five northeastern Scotland families previously identified by Southern blotting and detected affected members of five GRA families previously identified in Glasgow. A multiplex PCR protocol is described here that allows the control aldosterone synthase amplification and chimeric gene amplification to be carried out in the same tube. We describe the regions of cross-over in each of 10 kindreds identified in Scotland. To identify cross-over regions in each of the kindreds, the chimeric long PCR product was cloned and sequenced. Five cross-over sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of cross-over.

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				M. Hampf, N. T. N. Dao, N. T. Hoan, and R. Bernhardt Unequal Crossing-Over between Aldosterone Synthase and 11{beta}-Hydroxylase Genes Causes Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4445 - 4452. [Abstract] [Full Text] [PDF]