Previously it was shown that a missense mutation of Gly171 results in impaired binding of both sclerostin and DKK1 [9] and [14], which allows us to assume that deletion of this and its flanking amino acid will have a similar effect. This

supports the hypothesis that, besides the third β-propeller domain of LRP5 [10], the first β-propeller domain of the protein also has a critical role in the binding of sclerostin and DKKs. In accordance with the hypothesis raised by Bhat and colleagues [18] the deletion of the Gly171 and Glu172 residues could alter the three-dimensional structure of the receptor, thus determining a reduction in the affinity for its inhibitory ligands. Overall, this disease could be ascribed to a “gain of function” not with regard to the LRP5 protein itself, but to the entire signalling pathway, which turns out to be activated TSA HDAC in vitro even in the presence of its inhibitory factors. The proband herein described was a middle-aged woman who suffered

symptoms possibly related to the disease while in her teens, whereas the diagnosis of osteopetrosis was made at menopause when the clinical symptoms had started worsening. Her daughter was found to be osteopetrotic after radiological examination, however BTK inhibitor order she does not present any symptoms. Although it is likely that she carries the same mutation as her mother, confirmation through molecular analysis was not possible. Our data, together with those already reported in the literature, conclude that at variance with ADO II, in which several cases of early onset of the disease are documented [19] and [20], ADO I symptoms most frequently arise in adulthood, after the first radiological signs. In addition, ADO I patients do not display impairment of the haematological compartment,

even though the canonical Wnt signalling is known to play an important role in haematopoiesis, and rarely present visual deficits, while these defects can be very evident in some ADO II patients. Interestingly, our patient did show a complete Methane monooxygenase and abrupt occurrence of blindness at early age, although the exact cause could not be documented at that time (more than 40 years ago). All these findings confirm the original observation of Bollerslev and Andersen [1] that ADO I and ADO II are two distinct entities both from a clinical and molecular point of view. The canonical Wnt signalling has been reported to regulate key checkpoints in the development of many tissues, and among them, also in lymphopoiesis [21]. Even though in other forms of osteopetrosis both primary and secondary immunological defects have been described, no impairment of the immune system has been documented in ADO I patients, including ours, possibly due to the high redundancy of this pathway.