scholarly journals Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

2017 ◽  
Vol 33 (1) ◽  
pp. 32-41 ◽  
Author(s):  
Caroline M Gorvin ◽  
Fadil M Hannan ◽  
Treena Cranston ◽  
Helena Valta ◽  
Outi Makitie ◽  
...  
Keyword(s):  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function

scholarly journals A G‐protein Subunit‐α11 Loss‐of‐Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

2016 ◽  
Vol 31 (6) ◽  
pp. 1200-1206 ◽  
Author(s):  
Caroline M Gorvin ◽  
Treena Cranston ◽  
Fadil M Hannan ◽  
Nigel Rust ◽  
Asjid Qureshi ◽  
...  
Keyword(s):  
G Protein ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Protein Subunit

GNA11 loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2)

2013 ◽  
pp. 1-1
Author(s):  
Fadil Hannan ◽  
M A Nesbit ◽  
Sarah Howles ◽  
Valerie Babinsky ◽  
Treena Cranston ◽  
...  
Keyword(s):  
Loss Of Function

scholarly journals Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)

2020 ◽  
Vol 105 (5) ◽  
pp. 1393-1400
Author(s):  
Poonam Dharmaraj ◽  
Caroline M Gorvin ◽  
Astha Soni ◽  
Nick D Nelhans ◽  
Mie K Olesen ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Mutational Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Hydrogen Bond Interaction ◽  
Benign Condition ◽  
Neonatal Hypocalcemia

Abstract Context Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. Objective The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1. Methods A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent. Results The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. Conclusions Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.

scholarly journals Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

2019 ◽  
Vol 11 (475) ◽  
pp. eaau3441 ◽  
Author(s):  
Adrian Vella ◽  
Jennifer L. R. Freeman ◽  
Imogene Dunn ◽  
Kit Keller ◽  
John B. Buse ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Lipids ◽  
Regulatory Protein ◽  
Density Lipoprotein ◽  
Loss Of Function ◽  
Therapeutic Success ◽  
Double Blind ◽  
Glucokinase Activator ◽  
Clinically Significant

The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.

scholarly journals Gonadotrope-specific deletion of the BMP type 2 receptor does not affect reproductive physiology in mice†‡

2019 ◽  
Vol 102 (3) ◽  
pp. 639-646 ◽  
Author(s):  
Luisina Ongaro ◽  
Xiang Zhou ◽  
Yiming Cui ◽  
Ulrich Boehm ◽  
Daniel J Bernard
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Reproductive Organ ◽  
Conditional Knockout ◽  
Type Ii ◽  
Loss Of Function ◽  
Estrous Cyclicity ◽  
Transcription In Vitro

Abstract Activins selectively stimulate follicle-stimulating hormone (FSH) secretion by pituitary gonadotrope cells. More recently, other members of the TGFbeta superfamily, the bone morphogenetic proteins (BMPs), were reported to regulate FSH synthesis. Activins and BMPs independently and synergistically stimulate transcription of the FSHbeta subunit (Fshb) gene in immortalized gonadotrope-like cells. Both ligands can signal via the activin receptor type IIA (ACVR2A) to regulate FSH synthesis in vitro. In vivo, global Acvr2a knockout mice exhibit a 60% reduction in circulating FSH relative to wild-type animals, suggesting that activins, BMPs, or related ligands might signal through additional type II receptors to regulate FSH in vivo. Although the leading candidates are ACVR2B and the BMP type II receptor (BMPR2), only the latter mediates activin or BMP2 induction of Fshb transcription in vitro. Here, we generated mice carrying a loss of function mutation in Bmpr2 specifically in gonadotropes. Puberty onset, estrous cyclicity, and reproductive organ weights were similar between control and conditional knockout females. Serum FSH and luteinizing hormone (LH) and pituitary expression of Fshb and the LHbeta subunit (Lhb) were similarly unaffected by the gene deletion in both sexes. These results suggest that BMPR2 might not play a necessary role in FSH synthesis or secretion in vivo or that another type II receptor, such as ACVR2A, can fully compensate for its absence. These data also further contribute to the emerging concept that BMPs may not be physiological regulators of FSH in vivo.

scholarly journals Calcium Signaling Regulates Trafficking of Familial Hypocalciuric Hypercalcemia (FHH) Mutants of the Calcium Sensing Receptor

2012 ◽  
Vol 26 (12) ◽  
pp. 2081-2091 ◽  
Author(s):  
Michael P. Grant ◽  
Ann Stepanchick ◽  
Gerda E. Breitwieser
Keyword(s):  
Plasma Membrane ◽  
Steady State ◽  
State Level ◽  
Membrane Targeting ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Dynamic Changes ◽  
Calcium Sensing

Abstract Calcium-sensing receptors (CaSRs) regulate systemic Ca2+ homeostasis. Loss-of-function mutations cause familial benign hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). FHH/NSHPT mutations can reduce trafficking of CaSRs to the plasma membrane. CaSR signaling is potentiated by agonist-driven anterograde CaSR trafficking, leading to a new steady state level of plasma membrane CaSR, which is maintained, with minimal functional desensitization, as long as extracellular Ca2+ is elevated. This requirement for CaSR signaling to drive CaSR trafficking to the plasma membrane led us to reconsider the mechanism(s) contributing to dysregulated trafficking of FHH/NSHPT mutants. We simultaneously monitored dynamic changes in plasma membrane levels of CaSR and intracellular Ca2+, using a chimeric CaSR construct, which allowed explicit tracking of plasma membrane levels of mutant or wild-type CaSRs in the presence of nonchimeric partners. Expression of mutants alone revealed severe defects in plasma membrane targeting and Ca2+ signaling, which were substantially rescued by coexpression with wild-type CaSR. Biasing toward heterodimerization of wild-type and FHH/NSHPT mutants revealed that intracellular Ca2+ oscillations were insufficient to rescue plasma membrane targeting. Coexpression of the nonfunctional mutant E297K with the truncation CaSRΔ868 robustly rescued trafficking and Ca2+ signaling, whereas coexpression of distinct FHH/NSHPT mutants rescued neither trafficking nor signaling. Our study suggests that rescue of FHH/NSHPT mutants requires a steady state intracellular Ca2+ response when extracellular Ca2+ is elevated and argues that Ca2+ signaling by wild-type CaSRs rescues FHH mutant trafficking to the plasma membrane.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): Genotype and phenotype characteristics in a cohort of 197 patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1580-1580
Author(s):  
Ana Beatriz Sanchez-Heras ◽  
Adela Castillejo ◽  
Juan de Dios García-Diaz ◽  
Mercedes Robledo ◽  
Alex Teule ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Cell Cancer ◽  
Fumarate Hydratase ◽  
Stage Iv ◽  
Renal Cysts ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Pathogenic Variants

1580 Background: HLRCC is a hereditary condition with autosomal dominant inheritance due to germline mutations in the fumarate-hydratase gene ( FH). It is characterized by skin leiomyomas (SLM) in 48-84% of individuals, uterine leiomyomas (ULM) in 30-72%, renal cysts (RCy) and renal cell cancer (RCC) in 15-34%. We aimed to describe the genetics, the clinical features and the potential genotype-phenotype associations in the largest cohort of FH mutation carriers from Spain. Methods: We performed a multicenter, observational, retrospective study of individuals with genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records. We analyzed genetic variants and looked for genotype-phenotype associations. Statistical analyses were performed by IBM-SPSS Statistics-v.22. Results: We included 197 individuals (113 women, 84 men), 74 index cases and 123 relatives. Twenty-seven different variants were detected, 26 pathogenic (12 missense, 5 frameshift, 4 large-deletions, 3 splice-site and 2 nonsense) and 1 variant of unknown significance (missense). Of 182 patients with full skin examination, 64.8% presented SLM (median age 36 years; range 8-85). ULM were diagnosed in 90.3% of 103 women with gynecologic exam (median age 30 years; range 17- 55). Hysterectomy was performed in 62.9% (median age 34 years; range 21-54). Of 153 patients with radiological records, 37.3 % presented RCy. Nineteen patients (10.9%) presented RCC, 11 males and 8 females (median age 37 years; range 10-67). The histological diagnoses were: 14 papillary, of which 10 were type 2; 3 clear cell carcinoma and 2 unclassified carcinoma. Six tumors had stage I, 2 stage II, 3 stage III, 4 stage IV, and 4 not available. The median overall survival among patients at stages 3-4 was 2.9 years [1.3-4.5]. Patients with missense pathogenic variants showed higher risk of developing SLM (p = 0.043) and ULM (p = 0.002) than those with loss of function variants. Conclusions: In our cohort, the frequency of RCC (10.9%) is lower than that published in cohorts of similar sample size. The most frequent histology was the papillary type-2; however, other histological patterns do not exclude HLRCC. Individuals with missense pathogenic variants show higher incidence of SLM and ULM.

scholarly journals Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis

2016 ◽  
Vol 57 (3) ◽  
pp. R127-R142 ◽  
Author(s):  
Fadil M Hannan ◽  
Valerie N Babinsky ◽  
Rajesh V Thakker
Keyword(s):  
G Protein ◽  
Hormone Secretion ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Loss Of Function ◽  
Mineral Density ◽  
Gain Of Function ◽  
Type 3

The extracellular calcium (Ca2+o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca2+o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca2+o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH). However, CASR mutations are only detected in ≤70% of FHH and ADH cases, referred to as FHH type 1 and ADH type 1, respectively, and studies in other FHH and ADH kindreds have revealed these disorders to be genetically heterogeneous. Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein α-11 (Gα11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2σ) subunit, cause FHH type 3. These studies have demonstrated Gα11 to be a key mediator of downstream CaSR signal transduction, and also revealed a role for AP2σ, which is involved in clathrin-mediated endocytosis, in CaSR signalling and trafficking. Moreover, FHH type 3 has been demonstrated to represent a more severe FHH variant that may lead to symptomatic hypercalcaemia, low bone mineral density and cognitive dysfunction. In addition, calcimimetic and calcilytic drugs, which are positive and negative CaSR allosteric modulators, respectively, have been shown to be of potential benefit for these FHH and ADH disorders.

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