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

Abstract

XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotidebinding protein (Gsα), is paternally expressed. The significance of XLαs 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 XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, 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 XLαs 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 XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass. K E Y W O R D S hypophosphatemia, osteopetrosis, parathyroid hormone, pseudohypoparathyroidism, XLαs

Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner

“…The phenotypes associated with matUPD20 are similar to those observed in children with large paternal GNAS deletions (Aldred et al, 2002;Genevieve et al, 2005) and thus attributed largely to XLαs deficiency. Moreover, a recent study described an adult patient with hypophosphatemia and osteopetrosis who carried a nonsense mutation within the first XLαs exon (Chen et al, 2020). This defect was also paternally inherited, consistent with the evidence that XLαs is expressed from the paternal allele.…”

GNAS gene mutations affecting XLαs and bone health: A long neglected relationship

“…39,40 Our group has previously reported that the Gnasxl first exon paternal point mutation c.424G > T (p.G142*) resulted in a nonsense mutation in XLαs and a synonymous mutation in ALEX in a proband; his father and daughter also did not have a suckling disorder. 10 A polymorphism in the first exon encoding XLαs and ALEX was found to reduce the affinity between XLαs and ALEX proteins, increasing the activation of XLαs on the platelet plasma membrane and leading to an increased bleeding tendency. However, some of those patients have feeding difficulties, hypotonia, growth retardation, mental retardation, and short fingers.…”

“…38 SaOS 2 cells transfected with an XLαs deletion mutant showed significantly reduced levels of cAMP after PTH stimulation compared to cells transfected with normal XLαs. 10 Moreover, the response times of cAMP production by activated XLαs and Gsα proteins following stimulation differed, and cells transfected with XLαs showed a significantly longer cAMP response than Gsα-transfected cells when induced by the parathyroid hormone analog M-PTH. In transfected cells, full-length human XXLαs was localized to the plasma membrane and mediated isoproterenol-and cholera toxin-stimulated cAMP accumulation.…”

“…Patients with a nonsense mutation in the first exon of XLαs present with bilateral femoral neck fractures and a significantly reduced number of induced osteoclasts in peripheral blood mononuclear cells in culture in vitro. 10 Diseases with increased bone formation due to increased Wnt pathway activity 63,64 or transforming growth factorβ(TGF-β) 65 activating mutations have a low incidence of fractures. 66 In contrast, osteosclerosis due to reduced osteoclast activity is prone to recurrent fractures, such as autosomal dominant hereditary osteopetrosis type II 67 or pycnodysostosis.…”

“…[7][8][9] A patient with a nonsense mutations in the first exon of XLαs transcript exhibit fractures and osteopetrosis. 10 However, the first exon of Gnasxl transcript (transcribe XLαs and ALEX) knockout mouse indicates that XLαs paternal defects may be associated with growth retardation and impaired suckling. 11,12 Overall, the function of the XLαs transcript of GNAS gene is not known.…”