SGK3 – Hypophosphatemic Rickets

Hypophosphatemic rickets (HR) comprises hereditary disorders of renal phosphate wasting leading to rickets and osteomalacia. Classic causative genes include PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, and SLC34A3. A novel regulator, SGK3, has been implicated in an autosomal dominant form of HR [PMID:31821448]. The disease entity is represented as Hypophosphatemic Rickets.

In a single large pedigree with 5 affected individuals, exome sequencing identified a heterozygous intronic splice-site mutation c.979-96T>A in SGK3. This variant perfectly segregated with disease status and was absent in unaffected relatives (5 affected, 0 unaffected) ([PMID:31821448]).

Functional analysis of patient RNA showed that c.979-96T>A activates a cryptic splice site resulting in skipping of exon 13 and an in-frame deletion of 29 amino acids within the kinase domain, including the critical Thr-320 phosphorylation site. In silico tertiary structure modeling predicts significant conformational disruption of the kinase catalytic core, consistent with loss of SGK3 activation ([PMID:31821448]).

No other unrelated probands have been reported to date. The variant spectrum is limited to this single intronic splice mutation. The inheritance pattern is clearly autosomal dominant, with complete penetrance in the pedigree described.

Mechanistically, the deletion within the protein kinase domain likely impairs SGK3-mediated phosphorylation of renal phosphate transporters, leading to renal phosphate loss and rickets. Additional cellular or animal models of this specific SGK3 alteration have not yet been reported.

Taken together, the evidence supports a Limited clinical validity for the SGK3–Hypophosphatemic Rickets association based on a single kindred with robust segregation and structural modeling. Further studies are required to confirm pathogenicity in unrelated families. Key take-home: SGK3 c.979-96T>A should be considered in autosomal dominant HR diagnostic panels when common genes are negative.

References

• The Journal of clinical endocrinology and metabolism • 2020 • Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets. PMID:31821448

Evidence Based Scoring (AI generated)