Since a 3-kb deletion removing exons 4-6 of the STX16 locus has been identified in numerous familial PHP-Ib cases, and since this locus, with its exon-intron structure and its proximity to the GNAS locus, is similar in mice and humans, an attempt at generating a PHP-Ib mouse model has been made through targeted deletion of Stx16 exons 4-6 [167]. Both heterozygous and homozygous mice with this deletion lack gross abnormalities, are fertile, and appear to have a normal life span. More important, regardless of the parental origin of the deletion, the mutant mice fail to phenocopy the epigenetic abnormalities found in patients with familial PHP-Ib. In fact, neither any other Gnas methylation defects nor any biochemical features that would suggest PTH resistance could be observed in these animals. Thus, the nearly exact change in the mouse Stx16 gene is not sufficient to disrupt Gnas imprinting and to result in PTH resistance, ruling out a disrupted STX16 mRNA and/or protein as the molecular cause of familial PHP-Ib. This conclusion, which is consistent with the evidence that the STX16 locus is not
