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a Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA b Pediatric Nephrology Unit, MassGeneral Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Key Words: pseudohypoparathyroidism (PHP) • PHP type Ia (PHP-Ia) • pseudo-PHP (pPHP) • PHP type Ib (PHP-Ib) • progressive osseous heteroplasia (POH) •  -subunit of stimulatory G protein (Gs) • syntaxin 16 (STX16)
Address for correspondence: Harald Jüppner, M.D., Endocrine Unit, Thier 5, Massachusetts General Hospital, Boston, MA 02114. Voice: 617-726-3966; fax: 617-726-7543. e-mail: hjueppner{at}partners.org
The term pseudohypoparathyroidism (PHP) refers to the different disorders that are caused by mutations within GNAS or upstream of this complex genetic locus. GNAS gives rise to several different transcripts, including Gs
(-subunit of heterotrimeric stimulatory G protein), XLs (extra-large variant of Gs), and several additional sense and antisense transcripts. The complexity of the GNAS locus is furthermore reflected by a parent-specific methylation pattern of most of its different promotors. PHP can be divided into two major groups, PHP type Ia (PHP-Ia) and PHP type Ib (PHP-Ib). PHP-Ia is caused by heterozygous mutations affecting one of the 13 GNAS exons encoding Gs or by large intragenic deletions. In contrast, PHP-Ib is caused by heterozygous deletions within STX16, the gene-encoding syntaxin 16, which is located more than 220 kb upstream of GNAS, or by deletions within GNAS involving exon NESP55 and two of the antisense exons. In either form of PHP, hormonal resistance develops only after maternal inheritance of the mutation, while paternal inheritance of the same molecular defect is not associated with endocrine abnormalities. In most familial cases of PHP-Ib, there is a loss of exon A/B methylation combined with active A/B transcription from both parental alleles, which leads to suppression of Gs transcription in the proximal renal tubules and, therefore, PTH resistance.
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