Genetics of pseudohypoparathyroidism types Ia and Ic

Pseudohypoparathyroidism (PHP) types Ia and Ic result from heterozygous inactivating mutations of Gs alpha, the alpha-subunit of the heterotrimeric stimulatory G-protein, Gs. Both are characterized by a combination of Albright's hereditary osteodystrophy and, when the mutation is maternally inherited, end-organ resistance to multiple hormones. Due to complex tissue-specific imprinting of Gs alpha, paternally-derived mutations do not usually lead to hormone resistance. More than 100 mutations have been characterized in patients with PHP-Ia and one mutation in type Ic. These are scattered throughout the gene, with one significant mutational hotspot in exon 7. Identification of mutations in a clinical service setting is important for accurate genetic counselling and clinical management of affected families. However, only 70-80% of mutations are identified by direct sequencing of coding exons and splice junctions. Screening for whole exon deletions and intronic or regulatory mutations in mutation-negative families is therefore now an important priority to establish the full mutational spectrum in these conditions.