Preproparathyroid hormone (preproPTH) gene mutation has been proposed as a cause of familial isolated hypoparathyroidism (FIH). We cloned the preproPTH alleles of a patient with autosomal dominant FIH and sequenced the coding regions, 5' flanking regions, and splice junctions. The putatively abnormal (based on previous linkage studies) allele differed from the other allele's normal sequence at only one nucleotide. This T to C point mutation changes the codon for position 18 of the 31 amino acid prepro sequence from cysteine to arginine, disrupting the hydrophobic core of the signal sequence. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum, the mutant protein is likely to be inefficiently processed. Indeed, in vitro studies demonstrated dramatically impaired processing of the mutant preproPTH to proPTH.In summary, we observed a point mutation in the signal peptide-encoding region of a preproPTH gene in one FIH kindred and demonstrated a functional defect caused by the mutation. Mutation of the signal sequence constitutes a novel pathophysiologic mechanism in man, and further study may yield important insights both into this form of hormone deficiency and into the role of signal sequences in human physiology. (J. Clin. Invest. 1990.86:1084-1087

A preproparathyroid hormone allele from a patient with familial isolated hypoparathyroidism was shown to have a single point mutation in the hydrophobic core of the signal sequence. This mutation, changing a cysteine to an arginine codon at the -8 position of the signal peptide, was associated with deleterious effects on the processing of preproparathyroid hormone to proparathyroid hormone in vitro. To examine the biochemical consequence(s) of this mutation, proteins produced by cell-free translation of wild-type and mutant cRNAs were used in assays that reconstitute the early steps of the secretory pathway. We find that the mutation impairs interaction of the nascent protein with signal recognition particle and the translocation machinery. Moreover, cleavage of the mutant signal sequence by solubilized signal peptidase is ineffective. The consequence of this mutation on processing and secretion of parathyroid hormone is confirmed in intact cells by pulse-chase experiments following transient expression of the mutant protein in COS-7 cells. The inability of the mutant signal sequence, however, to interfere with the targeting and processing of other secreted proteins does not support obstruction of the translocation apparatus as the mechanism underlying the dominant mode of inheritance of hypoparathyroidism in this family.

The LD-100 system is a useful bone densitometry device and the database of age-related changes in TBD, CoTh, and EMTb established in this study will provide fundamental data for future studies related to bone status.

Folie à deux (FAD) was first described in 19th century France. Since then, the concept has been elaborated, and several subtypes of FAD have been successively reported in France. In contrast, studies in German-speaking psychiatry mainly focused on the conceptual boundary between reactive/endogenous psychosis and etiological hypothesis (ie, psychogenesis vs genetic predisposition). In North America, Gralnick wrote a seminal review and redefined four subtypes of FAD by adopting the European classical concepts. More recently, "shared psychotic disorder" in DSM or "induced delusional disorder" in ICD-10 was branched off from FAD. However, several classical subcategories of FAD were not included in these recent definitions, the nosological significance of which should not be underestimated. We examined demographic data of FAD case reports published from the 19th to the 21st century and found that some of the earlier hypotheses, such as females being more susceptible, older and more intelligent individuals being more likely to be inducers, and sister-sister pairs being the most common relationship, were not supported. The controversial issue of the etiology of FAD-association of subjects or genetically driven psychosis-was re-examined in light of recent studies.

We evaluated the competitive inhibitory effect of intact PTH, the amino-terminal PTH(1-34) fragment, and a series of truncated carboxyl-terminal PTH fragments on the binding of internally 35S-labeled human PTH(1-84) ([35S]hPTH(1-84)) to osteoblastic cells (ROS 17/2.8), in order to identify the minimum and critical elements within the PTH molecule for the interaction with the binding sites specific for the carboxyl-terminal region of the hormone. When the amino-terminal region of the PTH molecule was truncated stepwise, hPTH(35-84), hPTH(53-84) and hPTH(69-84), but not hPTH(70-84), significantly inhibited the [35S]hPTH(1-84) binding. On the other hand, the simple deletion of the carboxyl-terminal glutamine at position 84 of hPTH(53-84) [hPTH(53-83)] resulted in blunting the inhibitory effect of the peptide on the [35S]hPTH(1-84) binding. Furthermore, hPTH(35-84), hPTH(53-84) and hPTH(69-84), but not hPTH(70-84) nor hPTH(53-83), augmented the inhibitory effect of the amino-terminal PTH fragment [hPTH(1-34)] on the [35S]hPTH(1-84) binding. Of special interest was that the combination of hPTH(1-34) and hPTH(35-84) reproduced the inhibitory effect of unlabeled hPTH(1-84) on the [35S]hPTH(1-84) binding, on an equimolar basis. The 69-84 region of the PTH molecule thus appears to be crucial for binding to the carboxyl-terminal specific binding sites for PTH in osteoblasts. The interaction of the amino-terminal and carboxyl-terminal regions of a PTH molecule with their own respective binding sites seemed to occur in a fairly independent manner.