A paternally inherited non-sense variant c.424G>T (p.G142*) in the first exon of XLs in an adult patient with hypophosphatemia and osteopetrosis

XL alpha s, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gs alpha), is paternally expressed. The significance of XL alpha s in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XL alpha s, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XL alpha s, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XL alpha s failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XL alpha s plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.