Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons.

Abnormalities in the parathyroid hormone (PTH) gene as a cause of hypoparathyroidism were evaluated by linkage analysis with DNA polymorphisms adjacent to the PTH gene in 8 families in which members were affected with familial isolated hypoparathyroidism (FIH). We found that in none of the 23 affected individuals was there absence of the parathyroid hormone gene or abnormal restriction patterns to suggest recognizable deletions, insertions, or rearrangements. To determine if subtle mutations within the PTH gene were associated with hypoparathyroidism in these families, we used the Pst I and Taq I restriction-site polymorphisms in linkage analysis as markers to differentiate between PTH alleles. In 4 families, affected sibs inherited different PTH gene alleles, implying that hypoparathyroidism was not due to an abnormality in the PTH gene. In 2 other families, linkage analysis was uninformative because of inability to differentiate between PTH alleles. In 2 families, concordance was found between the inheritance of hypoparathyroidism and specific PTH alleles in affected members, suggesting that in these families, hypoparathyroidism may be due to an alteration in or near the PTH structural gene. We conclude that FIH is a diverse group of disorders and is characterized by genetic and molecular heterogeneity. In some forms of FIH the mutation that leads to PTH deficiency does not lie within the region of the structural gene for PTH. Linkage analysis using DNA polymorphisms within the PTH gene is of benefit in identifying individuals with disorders of PTH secretion or synthesis in whom DNA sequencing and expression studies of the PTH gene might succeed in establishing the molecular basis of the disease.