A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS.

A unique heterozygous 3-kb microdeletion within STX16, a closely linked gene centromeric of GNAS, was previously identified in multiple unrelated kindreds as a cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib). We now report a novel heterozygous 4.4-kb microdeletion in a large kindred with AD-PHP-Ib. Affected individuals from this kindred share an epigenetic defect that is indistinguishable from that observed in patients with AD-PHP-Ib who carry the 3-kb microdeletion in the STX16 region (i.e., an isolated loss of methylation at GNAS exon A/B). The novel 4.4-kb microdeletion overlaps with the previously identified deletion by 1,286 bp and, similar to the latter deletion, removes several exons of STX16 (encoding syntaxin-16). Because these microdeletions lead to AD-PHP-Ib only after maternal transmission, we analyzed expression of this gene in lymphoblastoid cells of affected individuals with the 3-kb or the 4.4-kb microdeletion, an individual with a NESP55 deletion, and a healthy control. We found that STX16 mRNA was expressed in all cases from both parental alleles. Thus, STX16 is apparently not imprinted, and a loss-of-function mutation in one allele is therefore unlikely to be responsible for this disorder. Instead, the region of overlap between the two microdeletions likely harbors a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B, thus allowing normal G alpha(s) expression in the proximal renal tubules. In the presence of either of the two microdeletions, parathyroid hormone resistance appears to develop over time, as documented in an affected individual who was diagnosed at birth with the 4.4-kb deletion of STX16 and who had normal serum parathyroid hormone levels until the age of 21 mo.