Epigenetic Changes and Pseudohypoparathyroidism Type Ib in Mice with Targeted Disruption of Syntaxin-16

Pseudohypoparathyroidism type Ib (PHP-Ib) is characterized by hypocalcemia and hyperphosphatemia due to proximal renal tubular resistance to PTH but without evidence for Albright´s hereditary osteodystrophy. The disorder is paternally imprinted and affected individuals, but not unaffected carriers, show loss of GNAS exon A/B methylation, a differentially methylated region upstream of the exons encoding Gsalpha. Affected individuals of numerous unrelated kindreds with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) have an identical 3-kb microdeletion removing exons 4-6 of syntaxin-16 (STX16) (STX16del4-6), which is thought to disrupt a cis-acting element required for exon A/B methylation. To explore the mechanisms underlying the regulation of exon A/B methylation, we generated mice genetically altered to carry the equivalent of STX16del4-6 (Stx16del4-6). Although the human GNAS locus shows a similar organization as the murine Gnas ortholog and although the human and mouse STX16/Stx16 regions show no major structural differences, no phenotypic or epigenotypic abnormalities were detected in mice with Stx16del4-6 on one or both parental alleles. Furthermore,calcium and PTH levels in Stx16del4-6 mice were indistinguishable from those in wild-type animals, indicating that ablation of the murine equivalent ofhumanSTX16del4-6 does not contribute to the development of PTH resistance. The identification of a novel intragenic transcript from within the STX16/Stx16 locus in total RNA from kidneys of Stx16del4-6 mice and lymphoblastoid cell-derived RNA of a patient with AD-PHP-Ib raises the question whether this transcript contributes, if deleted or altered, to the development of AD-PHP-Ib in humans.

Zentrum für Biologische Wissenschaften