A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by
 AP2S1  mutation

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Abstract

Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the CASR, GNA11 and AP2S1 genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in AP2S1. The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the CASR gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of AP2S1 revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.

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Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Martin R. Pollak, Edward M Brown, Yah-Huei Wu Chou … (1993)

We demonstrate that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis. The Ca(2+)-sensing receptor belongs to the superfamily of seven membrane-spanning G protein-coupled receptors. Three nonconservative missense mutations are reported: two occur in the extracellular N-terminal domain of the receptor; the third occurs in the final intracellular loop. One mutated receptor identified in FHH individuals was expressed in X. laevis oocytes. The expressed wild-type receptor elicited large inward currents in response to perfused polyvalent cations; a markedly attenuated response was observed with the mutated protein. We conclude that the mammalian Ca(2+)-sensing receptor "sets" the extracellular Ca2+ level and is defective in individuals with FHH and NSHPT.

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Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3

M. Andrew Nesbit, Fadil M. Hannan, Sarah A. Howles … (2012)

Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis which internalises plasma membrane constituents such as G protein-coupled receptors (GPCRs) 1-3 . AP2, a heterotetramer of alpha, beta, mu and sigma subunits, links clathrin to vesicle membranes and binds to tyrosine-based and dileucine-based motifs of membrane-associated cargo proteins 1,4 . Here, we show that AP2 sigma subunit (AP2S1) missense mutations, which all involved the Arg15 residue (Arg15Cys, Arg15His and Arg15Leu) that forms key contacts with dileucine-based motifs of CCV cargo proteins 4 , result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular-calcium homeostasis disorder affecting parathyroids, kidneys and bone 5-7 These AP2S1 mutations occurred in >20% of FHH patients without calcium-sensing GPCR (CaSR) mutations which cause FHH1 8-12 . AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular-calcium and reduced CaSR endocytosis, likely through a loss of interaction with a C-terminus CaSR dileucine-based motif whose disruption also decreased intracellular signalling. Thus, our results reveal a new role for AP2 in extracellular-calcium homeostasis.

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Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.

Valerie N. Babinsky, R Head, Fadil M. Hannan … (2013)

Familial hypocalciuric hypercalcemia is a genetically heterogeneous disorder with three variants: types 1, 2, and 3. Type 1 is due to loss-of-function mutations of the calcium-sensing receptor, a guanine nucleotide-binding protein (G-protein)-coupled receptor that signals through the G-protein subunit α11 (Gα11). Type 3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which result in altered calcium-sensing receptor endocytosis. We hypothesized that type 2 is due to mutations effecting Gα11 loss of function, since Gα11 is involved in calcium-sensing receptor signaling, and its gene (GNA11) and the type 2 locus are colocalized on chromosome 19p13.3. We also postulated that mutations effecting Gα11 gain of function, like the mutations effecting calcium-sensing receptor gain of function that cause autosomal dominant hypocalcemia type 1, may lead to hypocalcemia. We performed GNA11 mutational analysis in a kindred with familial hypocalciuric hypercalcemia type 2 and in nine unrelated patients with familial hypocalciuric hypercalcemia who did not have mutations in the gene encoding the calcium-sensing receptor (CASR) or AP2S1. We also performed this analysis in eight unrelated patients with hypocalcemia who did not have CASR mutations. In addition, we studied the effects of GNA11 mutations on Gα11 protein structure and calcium-sensing receptor signaling in human embryonic kidney 293 (HEK293) cells. The kindred with familial hypocalciuric hypercalcemia type 2 had an in-frame deletion of a conserved Gα11 isoleucine (Ile200del), and one of the nine unrelated patients with familial hypocalciuric hypercalcemia had a missense GNA11 mutation (Leu135Gln). Missense GNA11 mutations (Arg181Gln and Phe341Leu) were detected in two unrelated patients with hypocalcemia; they were therefore identified as having autosomal dominant hypocalcemia type 2. All four GNA11 mutations predicted disrupted protein structures, and assessment on the basis of in vitro expression showed that familial hypocalciuric hypercalcemia type 2-associated mutations decreased the sensitivity of cells expressing calcium-sensing receptors to changes in extracellular calcium concentrations, whereas autosomal dominant hypocalcemia type 2-associated mutations increased cell sensitivity. Gα11 mutants with loss of function cause familial hypocalciuric hypercalcemia type 2, and Gα11 mutants with gain of function cause a clinical disorder designated as autosomal dominant hypocalcemia type 2. (Funded by the United Kingdom Medical Research Council and others.).

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Contributors

Felix Chi Kin Wong: Role: InvestigationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0001-5160-0063

Wai Sheung Wong: Role: Investigation

Jeffrey Sung Shing Kwok: Role: Investigation

Teresa Kam Chi Tsui: Role: Investigation

Kam Piu Lau: Role: InvestigationRole: Supervision

Michael Ho Ming Chan: Role: Supervision

Yuet Ping Yuen: Role: InvestigationRole: SupervisionRole: Writing – Review & Editing

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 9 September 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: 1612

Affiliations

[1 ]Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong

[2 ]Department of Medicine, North District Hospital, Sheung Shui, Hong Kong

[1 ]Department of Physiology, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France

[2 ]Paris Descartes University, Paris, France

[1 ]Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

[1 ]Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

Author notes

[a ] felix@ 123456cuhk.edu.hk

No competing interests were disclosed.

Competing interests: No competing interests were disclosed.

Author information

Felix Chi Kin Wong https://orcid.org/0000-0001-5160-0063

Article

DOI: 10.12688/f1000research.20344.1

PMC ID: 6826774

PubMed ID: 31723423

SO-VID: 350e4b14-027f-44c7-8cbd-5eb20ec12ace

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This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 5 September 2019

Funding

The author(s) declared that no grants were involved in supporting this work.

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A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by AP2S1 mutation

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Most cited references 14

Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3

Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia.

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