Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Sian E Piret, Caroline M Gorvin, Alistair T Pagnamenta, Sarah A Howles, Treena Cranston, Nigel Rust, M. Andrew Nesbit, Ben Glaser, Jenny C Taylor, Andreas E Buchs, Fadil M Hannan, Rajesh V Thakker

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormoneconcentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being causedby germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germlinegain-of-function mutations of G-protein subunit a-11 (Ga11). To date Ga11 mutations causing ADH2 have been reported in only fiveprobands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are notknown to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whomone also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340MetGa11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Threedimensionalmodeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal a5 helix, which may affectG-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant(Met340) Ga11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses followingstimulation with extracellular calcium, of the mutant Met340 Ga11 led to a leftward shift of the concentration-response curve with asignificantly (p
LanguageEnglish
Pages1207-1214
JournalJournal of Bone and Mineral Research
Volume31
Issue number6
Early online date28 Jan 2016
DOIs
Publication statusE-pub ahead of print - 28 Jan 2016

Fingerprint

Protein Subunits
GTP-Binding Proteins
Mutation
Calcium-Sensing Receptors
Keratoconus
Hypocalcemia
Exome
Calcium
Hypercalciuria
Hypoparathyroidism
Germ-Line Mutation
HEK293 Cells
Iran
Familial Hypercalciuric Hypocalcemia
Carrier Proteins
Proteins
Serum

Keywords

  • WHOLE-EXOME SEQUENCING
  • G-PROTEIN
  • CALCIUM
  • HYPOPARATHYROIDISM
  • KERATOCONUS

Cite this

Piret, Sian E ; Gorvin, Caroline M ; Pagnamenta, Alistair T ; Howles, Sarah A ; Cranston, Treena ; Rust, Nigel ; Nesbit, M. Andrew ; Glaser, Ben ; Taylor, Jenny C ; Buchs, Andreas E ; Hannan, Fadil M ; Thakker, Rajesh V. / Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2). In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 6. pp. 1207-1214.
@article{15493a0a0cb044fba3203ef3483fdfb7,
title = "Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)",
abstract = "Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormoneconcentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being causedby germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germlinegain-of-function mutations of G-protein subunit a-11 (Ga11). To date Ga11 mutations causing ADH2 have been reported in only fiveprobands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are notknown to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whomone also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340MetGa11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Threedimensionalmodeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal a5 helix, which may affectG-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant(Met340) Ga11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses followingstimulation with extracellular calcium, of the mutant Met340 Ga11 led to a leftward shift of the concentration-response curve with asignificantly (p",
keywords = "WHOLE-EXOME SEQUENCING, G-PROTEIN, CALCIUM, HYPOPARATHYROIDISM, KERATOCONUS",
author = "Piret, {Sian E} and Gorvin, {Caroline M} and Pagnamenta, {Alistair T} and Howles, {Sarah A} and Treena Cranston and Nigel Rust and Nesbit, {M. Andrew} and Ben Glaser and Taylor, {Jenny C} and Buchs, {Andreas E} and Hannan, {Fadil M} and Thakker, {Rajesh V}",
year = "2016",
month = "1",
day = "28",
doi = "10.1002/jbmr.2797",
language = "English",
volume = "31",
pages = "1207--1214",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
number = "6",

}

Piret, SE, Gorvin, CM, Pagnamenta, AT, Howles, SA, Cranston, T, Rust, N, Nesbit, MA, Glaser, B, Taylor, JC, Buchs, AE, Hannan, FM & Thakker, RV 2016, 'Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)', Journal of Bone and Mineral Research, vol. 31, no. 6, pp. 1207-1214. https://doi.org/10.1002/jbmr.2797

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2). / Piret, Sian E; Gorvin, Caroline M; Pagnamenta, Alistair T; Howles, Sarah A; Cranston, Treena; Rust, Nigel; Nesbit, M. Andrew; Glaser, Ben; Taylor, Jenny C; Buchs, Andreas E; Hannan, Fadil M; Thakker, Rajesh V.

In: Journal of Bone and Mineral Research, Vol. 31, No. 6, 28.01.2016, p. 1207-1214.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

AU - Piret, Sian E

AU - Gorvin, Caroline M

AU - Pagnamenta, Alistair T

AU - Howles, Sarah A

AU - Cranston, Treena

AU - Rust, Nigel

AU - Nesbit, M. Andrew

AU - Glaser, Ben

AU - Taylor, Jenny C

AU - Buchs, Andreas E

AU - Hannan, Fadil M

AU - Thakker, Rajesh V

PY - 2016/1/28

Y1 - 2016/1/28

N2 - Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormoneconcentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being causedby germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germlinegain-of-function mutations of G-protein subunit a-11 (Ga11). To date Ga11 mutations causing ADH2 have been reported in only fiveprobands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are notknown to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whomone also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340MetGa11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Threedimensionalmodeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal a5 helix, which may affectG-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant(Met340) Ga11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses followingstimulation with extracellular calcium, of the mutant Met340 Ga11 led to a leftward shift of the concentration-response curve with asignificantly (p

AB - Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormoneconcentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being causedby germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germlinegain-of-function mutations of G-protein subunit a-11 (Ga11). To date Ga11 mutations causing ADH2 have been reported in only fiveprobands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are notknown to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whomone also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340MetGa11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Threedimensionalmodeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal a5 helix, which may affectG-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant(Met340) Ga11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses followingstimulation with extracellular calcium, of the mutant Met340 Ga11 led to a leftward shift of the concentration-response curve with asignificantly (p

KW - WHOLE-EXOME SEQUENCING

KW - G-PROTEIN

KW - CALCIUM

KW - HYPOPARATHYROIDISM

KW - KERATOCONUS

U2 - 10.1002/jbmr.2797

DO - 10.1002/jbmr.2797

M3 - Article

VL - 31

SP - 1207

EP - 1214

JO - Journal of Bone and Mineral Research

T2 - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 6

ER -