Autosomal-Dominant Pseudohypoparathyroidism Type Ⅰb is Caused by Different Microdeletions Within or Upstream of the GNAS Locus

摘要

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 Gsα (α-subunit of heterotrimeric stimulatory G protein), XLαs (extra-large variant of Gsα), 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 Gsα 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 Gsα transcription in the proximal renal tubules and, therefore, PTH resistance.