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The renal Na + /phosphate (Pi) cotransporter Npt2 is expressed in the brush border membrane (BBM) of proximal tubular cells. We examined the effect of Npt2 gene knockout on age-dependent BBM Na + /Pi cotransport, expression of Na + /Pi cotransporter genes Npt1, Glvr-1, and Ram-1, and the adaptive response to chronic Pi deprivation. Na + /Pi cotransport declines with age in wild-type mice (Npt2 +/+ ), but not in mice homozygous for the disrupted Npt2 allele (Npt2 -/-). At all ages, Na + /Pi cotransport in Npt2 -/-mice is approximately 15% of that in Npt2 +/+ littermates. Only Npt1 mRNA abundance increases with age in Npt2 +/+ mice, whereas Npt1, Glvr-1, and Ram-1 mRNAs show an age-dependent increase in Npt2 -/-mice. Pi deprivation significantly increases Na + /Pi cotransport, Npt2 protein, and mRNA in Npt2 +/+ mice. In contrast, Pi-deprived Npt2 -/-mice fail to show the adaptive increase in transport despite exhibiting a fall in serum Pi. We conclude that (a) Npt2 is a major determinant of BBM Na + /Pi cotransport; (b) the age-dependent increase in Npt1, Glvr-1, and Ram-1 mRNAs in Npt2 -/-mice is insufficient to compensate for loss of Npt2; and (c) Npt2 is essential for the adaptive BBM Na + /Pi cotransport response to Pi deprivation.

Aicardi syndrome is a rare disorder characterized by absent corpus callosum, infantile spasms, and choriorentinal lacunae. It is sporadic in nature and affects only females, resulting in severe mental and physical handicap. It has been suggested that the disease is caused by a dominant X-linked mutation which occurs de novo in females, and is lethal in hemizygous male embryos. This mode of inheritance has been observed in a number of other rare syndromes. In these syndromes, when X inactivation is studied, a non-random pattern is usually found. We have studied the X inactivation pattern in ten female patients with Aicardi syndrome and their parents using the highly polymorphic, differentially methylated androgen receptor gene. The results showed an unexpected random X-inactivation pattern in these patients. Previous clinical and cytogenetic evidence suggests that Aicardi syndrome is caused by an X-linked dominant mutation, de novo in females and lethal in males. However, unlike most other known X-linked disorders inherited in this fashion, Aicardi syndrome patients have a normal (i.e., random) X-inactivation pattern. A number of possible explanations is proposed for this apparently contradictory evidence.

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