Polycystic kidney disease 1 (PKDI) is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease. We have studied PKDI mRNA, with an RNase protection assay, and found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein, polycystin, was assessed in kidney using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining is restricted to epithelial cells. Expression in the developing nephron is most prominent in mature tubules, with lesser staining in Bowman's capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal was observed in comma-and S-shaped bodies as well as the distal branches of the ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no staining. In later fetal (>20 weeks) and adult kidney, strong staining persists in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. These results suggest that polycystin's major role is in the maintenance of renal epithelial differentiation and organization from early fetal life. Interestingly, polycystin expression, monitored at the mRNA level and by immunohistochemistry, appears higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein.

A second gene for autosomal dominant polycystic kidney disease (ADPKD) , PKD2, has been recently identified. Using antisera raised to the human PKD2 protein , polycystin-2 , we describe for the first time its distribution in human fetal tissues , as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein , polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1 , with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver , lung , bowel , brain , reproductive organs, placenta , and thymus. Of interest , nonepithelial cell types such as vascular smooth muscle , skeletal muscle , myocardial cells , and neurons also express both proteins. In PKD2 cystic kidney and liver , we find polycystin-2 expression in the majority of cysts, although a significant minority are negative , a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts , but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2؉/؊ mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that hetero- Renal cysts are the primary cause of morbidity in autosomal dominant polycystic kidney disease (ADPKD) but it is evident that the disease phenotype extends beyond the kidney. Cysts are commonly found in the liver and pancreas and have been reported in testis, spleen, ovary, uterus, esophagus, and brain. Moreover, abnormalities suggestive of a generalized disorder of connective tissue, including cardiac valvular abnormalities (especially mitral valve prolapse), intracranial berry aneurysms, colonic diverticulae, inguinal hernia, and a family with Marfanoid habitus, have been described. 1,2 Mutations in two genes, PKD1 and PKD2, account for the vast majority of patients with ADPKD. The identification of these genes 3,4 has thus provided a new opportunity to study the pathophysiology of ADPKD. The predicted proteins appear quite different in structure (the PKD1 protein, polycystin-1, is ϳ4 times larger than its counterpart, polycystin-2 4,5 ). Nonetheless, they share a significant region of homology in their transmembrane regions, an area also similar to a family of voltage-gated calcium/sodium channels. 4,6 Recent evidence indicates that the ADPKD proteins may interact in experimental systems. 7,8 PKD2 is less prevalent than PKD1, accounting for ϳ15% of ADPKD cases, 9,10 but preliminary evidence suggests they share the same spectrum of extrarenal manifestations. In one st...

Objectives-Both genetic and environmental risk factors for Alzheimer's disease have been identified. The best established environmental risk factor, head trauma, is thought to act through the triggering of an inflammatory response. Another stimulus to an inflammatory response in the brain is AIDS. Whether there is an increased prevalence of /A4 amyloid deposits in the form of argyrophilic plaques in the brains of patients with AIDS has therefore been investigated. Methods-The prevalence of argyrophilic amyloid plaques in the cerebral cortex of frontal and temporal lobes was compared in 97 cases of AIDS dying at ages 30-69 years with that in 125 age matched, non-HIV infected controls. Results-In the control group, and in AIDS, the prevalence of plaques increased with age (p=0.005 and 0.048 respectively). There was a significantly greater prevalence of argyrophilic plaques in the AIDS group as a whole (29%) (p< 0.004) and in those in the fourth decade (18%) (p<0.014) than in control subjects (13% and 0% respectively). Conclusion-There is a predisposition to argyrophilic plaque formation in the brain in AIDS. The findings support the view that a stimulus to an inflammatory response in the brain favours argyrophilic plaque formation. The clinical relevance of our findings is, as yet, unclear. (J Neurol Neurosurg Psychiatry 1998;65:29-33)

If a two-hit mutational mechanism is operational, these results suggest that the majority of somatic mutations in adult PKD1 are likely to be missense changes. The low level of polycystin-1-negative cysts in the three "early-onset" cases, however, suggests that a somatic PKD1 mutation may not always be required for cyst formation.