Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-04-27
2003-04-22
Zitomer, Stephanie (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S024330
Reexamination Certificate
active
06551775
ABSTRACT:
TECHNICAL FIELD
The invention relates to the fields of detecting and treating homozygous and heterozygous genetic deficiencies in ion transport, particularly alterations in nucleic acid molecules and proteins that give rise to various forms of pseudohypoaldosteronism type-1 (PHA1). More specifically, the invention provides compositions and methods for determining whether an individual is affected by or carriers a mutation a gene that encodes a protein involved in ion transport.
BACKGROUND ART
Background
Pseudohypoaldosteronism type I (PHA1) is a rare salt wasting disease characterized by an often fulminate presentation in the neonatal period with dehydration, hyponatremia, hyperkalaemia, metabolic acidosis, failure to thrive and weight loss despite normal renal glomerular filtration and adrenal function (Cheek, D. et al.
Archives of Dis. in Childhood
33:252-256 (1958); Dillon, M. J. et al.
Archives of Dis. in Childhood
55:427-434 (1980); Popow, C., et al.
Acta Paediatr. Scand
. 77:136-141 (1988); Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986). PHA1 is suspected when these infants fail to respond to mineralocorticoids, and the diagnosis is supported by the finding of an elevated plasma aldosterone concentration and plasma renin activity (Dillon, M. J. et al.
Archives of Dis. in Childhood
55:427-434 (1980); Popow, C., et al.
Acta Paediatr. Scand
. 77:136-141 (1988); Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986). Treatment includes sodium chloride supplementation and treatment with an ion-binding resin or dialysis to reduce life-threatening hyperkalaemia (Cheek, D. et al.
Archives of Dis. in Childhood
33:252-256 (1958); Dillon, M. J. et al.
Archives of Dis. in Childhood
55:427-434 (1980); Popow, C., et al.
Acta Paediatr. Scand
. 77:136-141 (1988); Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986; Donnell, G. N., et al.
Am. J. Dis. Child
. 97:813-828 (1959); Mathew,
P. M., et al. Clinical Pediatrics
. 1:58-60 (1993)). Death in the neonatal period is common if the diagnosis is not made.
PHA1 kindreds showing both autosomal recessive and dominant transmission have been described (Hanukoglu,
A. J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991)). Cases in recessive kindreds typically show mineralocorticoid resistance in the kidney, sweat and salivary glands, and colonic mucosa (Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986; Hanukoglu, A.
J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991); Hanukoglu, A., et al.
J. Pediatr
. 125: 752-755 (1994); Hogg, R. J., et al.
Pediatric Nephrology
5:205-210 (1991)); where measured, parents of these cases have had normal aldosterone and renin levels (Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986; Hanukoglu,
A. J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991)). In contrast, kindreds supporting dominant transmission have also been reported, and in some of these have been shown to have disease limited to the kidney (Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986; Hanukoglu, A.
J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991); Limal, J. M., et al. Lancet 1:51 (1978); Hanukoglu, A., et al.
Lancet
1:1359 (1978)). Clinical signs and metabolic abnormalities of some patients improve in the first several years of life, allowing discontinuation of therapy (Cheek, D. et al.
Archives of Dis. in Childhood
33:252-256 (1958); Dillon, M. J. et al.
Archives of Dis. in Childhood
55:427-434 (1980); Speiser, P. W., Stoner, E. & New, M. I. Pseudohypoaldosteronism: a review and report of two new cases. In: Mechanisms and clinical aspects of steroid hormone resistance. (eds. Chrousos, G. P., Loriaux, D. T. & Lipsett, M. B.) 173-195. (Plenum Press, New York), 1986; Donnell, G. N., et al.
Am. J. Dis. Child
. 97:813-828 (1959); Hanukoglu, A.
J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991)); it has been suggested that these patients are most often those with dominant transmission (Hanukoglu, A.
J. Clin. Endocrin
. &
Metab
. 73,936-944 (1991)).
The pathogenesis of this syndrome has not been elucidated. The triad of renal salt wasting, hyperkalaemia and failure to respond to mineralocorticoids is most compatible with a renal defect in the distal nephron (Cheek, D. et al.
Archives of Dis. in Childhood
33:252-256 (1958); Rösler, A.
J. Clin. Endocrin
. &
Metab
. 59:689-700 (1984)). While mineralocorticoid receptor levels in affected patients have been found to be low (Armanini, D. et al.
N. Eng. J Med
. 313:1178-1181 (1985); Kuhnle U. et al.
J. Clin. Endocrin. & Metab
. 70:638-641 (1990); Bosson, D. et al. Acta Endo. 113:S376-S381 (1986)) molecular studies have revealed no evidence for a primary defect in the mineralocorticoid receptor (Komesaroff, P. A., et al.
J. Clin. Endocrin
. &
Metab.
79:27-31 (1994); Zennaro, M. C., et al.
J. Clin. Endocrin
. &
Metab
. 79:32-38 (1994)).
Electrogenic transepithelial sodium transport is the rate limiting step in sodium reabsorption in the distal nephron, the distal colon, salivary and sweat glands, and lung epithelia (Horisberger, J. D., et al.
Cell Physiol. Biochem
. 32:283-294 (1993)). In the kidney, this electrogenic sodium transport is positively regulated by aldosterone (Rossier, B. C. & Palmer, L. G. Mechanism of aldosterone action on sodium and potassium transport. In: The Kidney, physiology and pathophysiology (eds. Seldin, D. W. and Giebisch, G.) 1373-1409 (Raven Press, New York, 1992)) and is mediated by the amiloride-sensitive epithelial sodium channel (ENaC). This channel composed of at least three subunits of similar structure (Canessa, C. M., et al.
Nature
361:467-470 (1993); Canessa, C. M. et al.
Nature
367:463-467 (1994)), each with intracellular amino and carboxy termini, two transmembrane spanning domains, and a large extracellular loop. In humans, &agr;ENaC is present on human chromosome 12, while b and g are tightly linked on chromosome 1622.
Mutations resulting in constitutive activation of ENaC activity have been shown to cause an autosomal dominant form of hypertension, Liddle's syndrome (Shimkets, R. A. et al.
Cell
79:407-414 (1994); Hansson, J. H. et al.
Nature Genetics
11:76-82 (1995); Hansson, J. H. et al.
Proc. Nat. Acad. Sci. USA
92:11495-11499 (1995); Schild, L. et al.
Proc. Natn. Acad. Sci. USA
92:5699-5703 (1995)), which is characterized by volume expansion, hypokalaemia and alkalosis.
The present invention provides compositions and methods that can be used to differentiate and diagnose ion transport deficiencies, particularly PHA1. The present invention further provides methods and compositions that can be used to identify heterozygous carriers for this disorder. Carriers, though not displaying severe clinical symptoms, nonetheless display mild to moderate pathologies.
SUMMARY OF THE INVENTION
The present invention is based, in part, on the identification of th
Chang Sue S.
Lifton Richard P.
Rossier Bernard C.
Morgan & Lewis & Bockius, LLP
Yale University
Zitomer Stephanie
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