Different Forms of Pseudohypoparathyroidism: Imprinted Disorders Caused by Different Coding and Non-coding Mutations in GNAS

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Pseudohypoparathyroidism (PHP) refers to disorders that are elicited by coding and non-coding mutations in GNAS, a complex gene locus encoding the α-subunit of stimulatory G protein (Gsα) and splice variants thereof. The complexity of the GNAS locus is reflected by several alternatively spliced sense and antisense transcripts, a parent-specific methylation pattern and consequently transcription from only one parental allele for all mRNAs, except for the mRNA encoding Gsα. PHP can be divided into two major groups that are caused either by heterozygous mutations in exons affecting Gsα (PHP type Ia: PHP-Ia) or by deletions of presumably regulatory regions affecting GNAS (PHP type Ib: PHP-Ib). The former group comprises besides PHP-Ia, pseudo-PHP (pPHP), and progressive osseous heteroplasia (POH). The phenotypes of these disorders are quite different and depend on the kind of mutation and whether it is inherited maternally or paternally. For example, PHP-Ia develops after maternal inheritance of a Gsα mutation, while paternal inheritance of the same mutation leads to pPHP or POH. Similarly, maternal inheritance of a deletion in STX16, the gene encoding syntaxin 16, up-stream of GNAS leads to PHP-Ib, while inheritance of the same mutation from a male does not result in an obvious phenotype. In most familial cases of PHP-Ib, there is a loss of methylation affecting only exon A/B thus leading to active A/B transcription from both parental alleles, thereby suppressing Gsα transcription in the renal cortex and causing PTH-resistance.<br>

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