This study shows that mutations effecting Gα11 loss of function cause familial hypocalciuric hypercalcemia type 2, and mutations effecting Gα11 gain of function result in autosomal dominant ...hypocalcemia type 2. Important aspects of Gα11 function are also described.
Familial hypocalciuric hypercalcemia, an autosomal dominant disorder, is characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion (mean urinary calcium:creatinine clearance ratio, <0.01) and normal circulating parathyroid hormone concentrations in 80% of patients (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
1
–
3
Patients with familial hypocalciuric hypercalcemia are generally asymptomatic, although pancreatitis or chondrocalcinosis may develop in some affected adults.
4
Familial hypocalciuric hypercalcemia is genetically heterogeneous, with three reported variants. Type 1 is due to loss-of-function mutations of the calcium-sensing receptor (encoded by
CASR
), type 2 is . . .
The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors in association with ossifying fibromas of the maxilla ...and/or mandible. The gene responsible for HPT-JT, known as CDC73, was identified in 2002 and encodes a 531 amino acid protein known as parafibromin. Parafibromin is predominantly a nuclear protein that interacts directly with β-catenin and also forms part of the RNA polymerase associated factor-1 complex (Paf1C) that regulates transcription. Heterozygous germline CDC73 mutations are detected in the majority of patients with HPT-JT, and the demonstration of loss of heterozygosity (LOH) at the CDC73 locus in tumors from affected individuals is consistent with a tumor suppressor role. Somatic CDC73 mutations are a frequent finding in nonfamilial (i.e., sporadic) parathyroid carcinomas and have also been reported in benign sporadic parathyroid tumors as well as sporadic renal and fibro-osseous jaw tumors. To date, 111 independent CDC73 mutations have been identified (68 germline; 38 somatic; 5 undefined), and these occur throughout the coding region and splice sites of the CDC73 gene, with the majority (>80%) predicting premature truncation of the parafibromin protein. These CDC73 mutations, together with their clinical and biological relevance, are reviewed. Hum Mutat 31:295-307, 2010.
Context:
Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and ...GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2σ 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3.
Objective:
The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3.
Design:
The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1.
Results:
Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients.
Conclusion:
The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.
Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as G protein-coupled ...receptors (GPCRs). AP2, a heterotetramer of α, β, μ and σ subunits, links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membrane-associated cargo proteins. Here we show that missense mutations of AP2 σ subunit (AP2S1) affecting Arg15, which forms key contacts with dileucine-based motifs of CCV cargo proteins, result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular calcium homeostasis disorder affecting the parathyroids, kidneys and bone. We found AP2S1 mutations in >20% of cases of FHH without mutations in calcium-sensing GPCR (CASR), which cause FHH1. AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. Thus, our results identify a new role for AP2 in extracellular calcium homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective: Paragangliomas are rare tumors of neuroendocrine origin; approximately 30% of these tumors are related to an underlying genetic condition. Many of the hereditary paragangliomas, ...particularly those arising in the head and neck, have been linked to mutations in genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. The authors report an atypical presentation of a rare mutation in the SDH complex subunit C gene (SDHC).Methods: We reviewed the patient's clinical course, along with relevant literature for similar reported cases.Results: A 45-year-old woman with a background of multiple and recurrent paragangliomas (left glomus jugulare, right carotid body tumor, intrathyroidal and right lung paragangliomas) was found to have an intrapericardiac paraganglioma associated with excess levels of dopamine metabolites. Simultaneously, the proband's son was diagnosed with a macroprolactinoma at age 23 years. Genetic workup identified an underlying germline mutation in the gene encoding SDHC, consistent with the diagnosis of familial paraganglioma syndrome type 3. Current knowledge regarding the clinical implications of an SDHC gene mutation have been reviewed.Conclusion: Patients with SDHC gene mutations can develop paragangliomas within the pericardium. Our patient presented with multiple recurrent paragangliomas, in different locations, including within the pericardium. These tumors were functional, including a dopamine-secreting paraganglioma. The presence of multiple paragangliomas, the cardiac localization of tumors, the high risk of recurrence, and the elevation of 3-methoxytyramine levels should be taken into account when treating these patients. In addition, the diagnosis of macroprolactinoma in our patient's son reinforces the reported association between SDH mutations and the development of pituitary tumors.Abbreviations: MRI magnetic resonance imaging RET RET proto-oncogene SDH succinate dehydrogenase SDHB succinate dehydrogenase enzyme complex subunit B SDHC succinate dehydrogenase enzyme complex subunit C
Abstract
The calcium-sensing receptor (CaSR) is a homodimeric G-protein-coupled receptor that signals via intracellular calcium (Ca2+i) mobilisation and phosphorylation of extracellular ...signal-regulated kinase 1/2 (ERK) to regulate extracellular calcium (Ca2+e) homeostasis. The central importance of the CaSR in Ca2+e homeostasis has been demonstrated by the identification of loss- or gain-of-function CaSR mutations that lead to familial hypocalciuric hypercalcaemia (FHH) or autosomal dominant hypocalcaemia (ADH), respectively. However, the mechanisms determining whether the CaSR signals via Ca2+i or ERK have not been established, and we hypothesised that some CaSR residues, which are the site of both loss- and gain-of-function mutations, may act as molecular switches to direct signalling through these pathways. An analysis of CaSR mutations identified in >300 hypercalcaemic and hypocalcaemic probands revealed five 'disease-switch' residues (Gln27, Asn178, Ser657, Ser820 and Thr828) that are affected by FHH and ADH mutations. Functional expression studies using HEK293 cells showed disease-switch residue mutations to commonly display signalling bias. For example, two FHH-associated mutations (p.Asn178Asp and p.Ser820Ala) impaired Ca2+i signalling without altering ERK phosphorylation. In contrast, an ADH-associated p.Ser657Cys mutation uncoupled signalling by leading to increased Ca2+i mobilization while decreasing ERK phosphorylation. Structural analysis of these five CaSR disease-switch residues together with four reported disease-switch residues revealed these residues to be located at conformationally active regions of the CaSR such as the extracellular dimer interface and transmembrane domain. Thus, our findings indicate that disease-switch residues are located at sites critical for CaSR activation and play a role in mediating signalling bias
Context:
Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common ...pathogenic mechanism or a coincidence.
Objective:
The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.
Design:
Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.
Setting:
The study was conducted at university hospitals.
Patients:
Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.
Outcome:
Outcomes included genetic screening and clinical characteristics.
Results:
Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.
Conclusions:
Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.
PDF
