A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive Manner.
Ontology highlight
ABSTRACT:
SUBMITTER: Bastepe M
PROVIDER: S-EPMC6669810 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
A Gain-of-Function CASR Mutation Causing Hypocalcemia in a Recessive Manner.
The Journal of clinical endocrinology and metabolism 20180901 9
Similar Datasets
Project description:Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1-34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1-34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.
| S-EPMC8686169 | biostudies-literature
Project description:Autosomal dominant hypocalcemia, caused by activating mutations of the calcium-sensing receptor (CASR) gene, is characterized by hypocalcemia with an inappropriately low concentration of parathyroid hormone (PTH). In this report, we describe the identification of a novel missense mutation in the CASR gene, in a boy with autosomal dominant hypocalcemia. Polymerase chain reaction (PCR)-single strand and DNA sequencing revealed a heterozygous mutation in CASR gene that causes a leucine substitution for serine at codon 123 (p.Leu123Ser). This mutation was absent in DNA from 50 control patients. In silico studies suggest that the identified variant was likely pathogenic. Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected. Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later, namely, hand tremor and rigidity at the age of 7 and 18 years, respectively. Laboratory analysis revealed hypocalcemia, hyperphosphatemia, and low-serum PTH with hypomagnesemia and mild hypercalciuria. After 2 years of treatment with calcium supplements and calcitriol, some brief periods of clinical improvement were reported; as well as an absence of nephrocalcinosis.
| S-EPMC4906418 | biostudies-literature
Project description:Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder characterized by hypocalcemia with low parathyroid hormone (PTH) levels and high urinary calcium. Its clinical presentation varies from mild asymptomatic to severe hypocalcemia. It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney. Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant. We comprehensively analyzed the phenotypic features of this presentation and reviewed the current literature to better understand clinical manifestations and the genetic spectrum.
| S-EPMC9280832 | biostudies-literature
Project description:Mechanisms that regulate the growth and form of the vertebrate skeleton are largely unknown. The zebrafish mutant rapunzel has heterozygous defects in bone development, resulting in skeletal overgrowth, thus identification of the genetic lesion underlying rapunzel might provide insight into the molecular basis of skeletogenesis. In this report, we demonstrate that the rapunzel mutant results from a missense mutation in the previously uncharacterized rpz gene. This conclusion is supported by genetic mapping, identification of a missense mutation in rapunzel(c14) in a highly conserved region of the rpz gene, and suppression of the rapunzel homozygous embryonic phenotype with morpholino knockdown of rpz. In addition, rpz transcripts are identified in regions correlating with the homozygous embryonic phenotype (head, pectoral fin buds, somites and fin fold). This report provides the first gene identification for a mutation affecting segment number in the zebrafish fin and development of both the fin ray (dermal) and the axial skeleton.
| S-EPMC2756807 | biostudies-literature
Project description:Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder.
| S-EPMC4541614 | biostudies-literature
Project description:PurposeThe aim of the study was to characterize the underlying mutation in a consanguineous family having cataracts.MethodsFamily D having congenital cataracts was treated at the University Eye Clinics at Giessen (Germany). Lens material from surgeries was collected, immediately frozen at -80 degrees C, and used for cDNA production. Blood was taken from the proband and available family members. Polymerase chain reaction (PCR)-amplified DNA fragments were characterized by sequencing and restriction digestion.ResultsThe proband, AD, has a dense, triangular nuclear cataract. The parents are consanguineous, and the mother and grandmother suffer from a discrete, symmetric opacity of the fetal lens nucleus. The proband's lens cDNA showed a homozygous insertion of one G after position 776 of the GJA8 gene, leading to a frame shift and 123 novel amino acids. The homozygous mutation was confirmed in the genomic DNA and is also present in the cataract-operated brother of the proband; all other family members investigated were heterozygous. The mutation could not be detected in 96 healthy controls from Germany.ConclusionsThe ins776G mutation most likely causes a recessive triangular cataract with variable expressivity of a weak phenotype in heterozygotes.
| S-EPMC2375854 | biostudies-literature
Project description:Objective To present the clinical, genetic, biochemical, and molecular findings in two Chinese siblings with X-linked recessive Kallmann syndrome (KS). Design Case report. Setting University medical center. Patient(s) Two Chinese siblings. Intervention(s) Clinical evaluation, hormone assays, and gene mutation research. Main outcome measure(s) Endocrinologic evaluation and genetic analysis. Result(s) A missense mutation of KAL1, c.1828G>A, led to pVal610Ile substitution in two brothers with KS; their mother is heterozygous for this missense mutation encoded by single-nucleotide polymorphism rs2229013. Conclusions Mutation analysis revealed that a missense mutation of KAL1 in two brothers with KS, while their mother was heterozygous for this missense mutation encoded by the single-nucleotide polymorphism rs2229013. Variant alleles of KAL1 related to X-linked recessive KS expand the spectrum of KAL1 mutations causing KS.
| S-EPMC4708518 | biostudies-literature
Project description:Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germline gain-of-function mutations of G-protein subunit α-11 (Gα11 ). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three-dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal α5 helix, which may affect G-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration-response curve with a significantly (p < 0.0001) reduced mean half-maximal concentration (EC50 ) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild-type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain-of-function mutation. A novel His403Gln variant in transforming growth factor, beta-induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain-of-function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C-terminal region for G-protein function and CaSR signal transduction. © 2016 American Society for Bone and Mineral Research.
| S-EPMC4915495 | biostudies-literature
Project description:BACKGROUND: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3) subunit in humans. METHODS AND FINDINGS: We sequenced the exons and splice junctions of the AMPK gamma(3) gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3) R225W mutation is homologous in location to the gamma(2)R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3)R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG). CONCLUSIONS: We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3) subunit of AMPK in humans. The gamma(3)R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK gamma(3) in human muscle energy metabolism.
| S-EPMC1964808 | biostudies-literature
Project description:Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell-restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.
| S-EPMC8410089 | biostudies-literature