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

Endocrine Unit (L.F.F., M.B., D.O., H.A.-Z., H.J.) and Pediatric Nephrology Unit (H.J.), Department of Medicine and Massachusetts General Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Harald Jüppner, Endocrine Unit, Thier 10, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: jueppner{at}helix.mgh.harvard.edu.

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 Gs. 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 (Stx16^4–6). 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 Stx16^4–6 on one or both parental alleles. Furthermore, calcium and PTH levels in Stx16^4–6 mice were indistinguishable from those in wild-type animals, indicating that ablation of the murine equivalent of human STX16del4–6 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 Stx16^4–6 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.

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