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A paternally inherited non-sense variant c.424GT (p.G142*) in the first exon of XLαs in an adult patient with hypophosphatemia and osteopetrosis
- Source :
- Clinical geneticsREFERENCES. 97(5)
- Publication Year :
- 2019
-
Abstract
- XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding 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.
- Subjects :
- 0301 basic medicine
Adult
Male
medicine.medical_specialty
Parathyroid hormone
030105 genetics & heredity
Biology
Bone resorption
Bone remodeling
Cell Line
03 medical and health sciences
Osteoprotegerin
Internal medicine
Genetics
medicine
GNAS complex locus
GTP-Binding Protein alpha Subunits, Gs
Humans
Genetic Predisposition to Disease
Genetics (clinical)
Pseudohypoparathyroidism
Hypophosphatemia, Familial
Osteopetrosis
Exons
medicine.disease
030104 developmental biology
Endocrinology
Codon, Nonsense
Parathyroid Hormone
biology.protein
Paternal Inheritance
Hypophosphatemia
Subjects
Details
- ISSN :
- 13990004
- Volume :
- 97
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Clinical geneticsREFERENCES
- Accession number :
- edsair.doi.dedup.....85204d05606e3bfdceaa8d9f88055625