We report on two sisters (aged 44 and 51) from consanguineous parents who presented with tetany at birth and were diagnosed with congenital hypocalcaemia. Serum PTH levels were normal for many years, but have progressively increased over the past decade to greater than 100x ULN. A novel homozygous mutation in PTH was identified through homozygosity mapping. Several large regions of homozygosity were identified encompassing >1.7% of the genome. The most striking candidate calciotropic gene identified within a region of homozygosity was PTH. This was sequenced in Sister A and a p.Ser32Pro substitution was identified.
PreproPTH undergoes two proteolytic cleavages, first to proPTH and then mature PTH (1-84). The biological activity of PTH has been shown to reside fully within the amino-terminal 34 amino acids (i.e. PTH1-34 which is used therapeutically). Familial hypoparathyroidism has a heterogeneous presentation and includes mutations involving PTH, CASR and GCMB. In this condition, patients usually have low PTH levels due to impaired function or secretion of parathyroid hormone. This is in contrast to pseudohypoparathyroidism type 1a and 1b that reflects PTH resistance and is usually associated with high PTH levels. High levels of circulating PTH can be due to resistance (pseudohypoparathyroidism) or bioinactivity (mutations in PTH) and it can be difficult to distinguish between them biochemically
The substitution of Pro instead of Ser at the first amino acid in mature PTH suggests that PTH is still cleaved and secreted but non functional. The elevated PTH levels are support this. This is an important differential for patients with pseudohypoparathyroidism without established gene mutations. This case also demonstrates the utility of homozygosity mapping to rapidly identify candidate genes in rare conditions associated with consanguinity.