Context: Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-offunction mutations in CASR or dominant inhibitor mutations in GCM2 or PTH. Copyright
Objective: Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism.
Subjects: Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members.
Methods: Wecollected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant Gα11proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors.
Results: Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the α-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of Gα11R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type Gα11. By contrast, R60L was significantly less effective than the oncogenicQ209Lform ofGα11asanactivator of theMAPKpathway.Comparedto subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels.
Conclusions:Ourfindings indicate that the germline gain-of-function mutation ofGNA11is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.
ASJC Scopus subject areas
- Clinical Biochemistry
- Biochemistry, medical
- Endocrinology, Diabetes and Metabolism