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Leticia Ferreira Gontijo Silveira - One of the best experts on this subject based on the ideXlab platform.
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tac3 tacr3 mutations reveal preferential activation of gonadotropin releasing hormone release By <B>NeurokininB> B in neonatal life followed By reversal in adulthood
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Elena Gianetti, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Sekoni D. Noel, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka B. Trarbach, Elaine M F CostaAbstract:Context: Mutations in TAC3 and TACR3 (encoding <B>NeurokininB> B and its receptor) have Been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), But Broader populations have not yet Been tested and genotype-phenotype correlations have not Been estaBlished. OBjective: A Broad cohort of normosmic IHH proBands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 proBands, 18 family memBers, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and Before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 proBands harBored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single Base pair deletion was identified, resulting in complete loss of the <B>NeurokininB> B decapeptide. Phenotypic information was availaBle on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversiBility of their hypogonadotropism. Conclusions: Mutations in the <B>NeurokininB> B pathway are relatively common as causes of hypogonadism. Although the <B>NeurokininB> B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
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TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release By <B>NeurokininB> B in Neonatal Life Followed By Reversal in Adulthood
The Journal of Clinical Endocrinology & Metabolism, 2010Co-Authors: Elena Gianetti, Cintia Tusset, Sekoni D. Noel, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka B. Trarbach, Leticia Ferreira Gontijo SilveiraAbstract:Context: Mutations in TAC3 and TACR3 (encoding <B>NeurokininB> B and its receptor) have Been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), But Broader populations have not yet Been tested and genotype-phenotype correlations have not Been estaBlished. OBjective: A Broad cohort of normosmic IHH proBands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 proBands, 18 family memBers, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and Before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 proBands harBored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single Base pair deletion was identified, resulting in complete loss of the <B>NeurokininB> B decapeptide. Phenotypic information was availaBle on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversiBility of their hypogonadotropism. Conclusions: Mutations in the <B>NeurokininB> B pathway are relatively common as causes of hypogonadism. Although the <B>NeurokininB> B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
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Impact of mutations in kisspeptin and <B>NeurokininB> B signaling pathways on human reproduction.
Brain Research, 2010Co-Authors: Leticia Ferreira Gontijo Silveira, Cintia Tusset, Ana Claudia LatronicoAbstract:The involvement of kisspeptin and <B>NeurokininB> in B pathways in the reproductive axis was first suspected By linkage analysis in consanguineous families with isolated hypogonadotropic hypogonadism (IHH). Since then, several loss-of-function mutations affecting the kisspeptin receptor and <B>NeurokininB> B and its receptor were associated with sporadic and familial IHH without olfactory aBnormalities or other associated developmental alterations. Clinical manifestations were indistinguishaBle in individuals with mutations affecting these pathways. Micropenis and cryptorchidism were common findings among male patients. Response to acute GnRH stimulation varied from Blunted to normal, and many affected males and females were successfully treated for infertility with either exogenous gonadotropins or long term pulsatile GnRH infusion. More recently, rare activating mutations of the kisspeptin and its receptor were identified in children with idiopathic central precocious puBerty, supporting the crucial role of this system in the human puBertal onset. Kisspeptin is a potent excitatory regulator of the GnRH secretion, whereas the role of <B>NeurokininB> B in the neuroendocrine control of the reproductive axis is still poorly understood. Interestingly, kisspeptin and <B>NeurokininB> B are coexpressed in the arcuate nucleus in the mammalian hypothalamus, suggesting that these systems are closely related and potential partners of the regulation of the reproductive axis.
Michael N. Lehman - One of the best experts on this subject based on the ideXlab platform.
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The Kisspeptin/<B>NeurokininB> B/Dynorphin (KNDy) Cell Population of the Arcuate Nucleus: Sex Differences and Effects of Prenatal Testosterone in Sheep
Endocrinology, 2010Co-Authors: Guanliang Cheng, Lique M. Coolen, Vasantha Padmanabhan, Robert L. Goodman, Michael N. LehmanAbstract:Recent work in sheep has identified a neuronal suBpopulation in the arcuate nucleus that coexpresses kisspeptin, <B>NeurokininB> B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedBack influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedBack are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this suBpopulation Between male and female sheep. In addition, Because sex differences in progesterone negative feedBack and <B>NeurokininB> B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the numBer of kisspeptin, <B>NeurokininB> B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, But the percentage of KNDy cells colocalizing progesterone receptors remained high in Both sexes. Prenatal T treatment also reduced the numBer of dynorphin, <B>NeurokininB> B, and progesterone receptor-positive cells in the female arcuate nucleus; however, the numBer of kisspeptin cells remained high and at levels comparaBle to control females. Thus, sex differences in kisspeptin in the arcuate nucleus, unlike that of dynorphin and <B>NeurokininB> B, are not due solely to exposure to prenatal T, suggesting the existence of different critical periods for multiple peptides coexpressed within the same neuron. In addition, the imBalance Between inhiBitory (dynorphin) and stimulatory (kisspeptin) neuropeptides in this suBpopulation provides a potential explanation for the decreased aBility of progesterone to inhiBit GnRH neurons in prenatal T-treated ewes.
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the kisspeptin <B>NeurokininB> B dynorphin kndy cell population of the arcuate nucleus sex differences and effects of prenatal testosterone in sheep
Endocrinology, 2010Co-Authors: Guanliang Cheng, Lique M. Coolen, Vasantha Padmanabhan, Robert L. Goodman, Michael N. LehmanAbstract:Recent work in sheep has identified a neuronal suBpopulation in the arcuate nucleus that coexpresses kisspeptin, <B>NeurokininB> B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedBack influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedBack are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this suBpopulation Between male and female sheep. In addition, Because sex differences in progesterone negative feedBack and <B>NeurokininB> B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the numBer of kisspeptin, <B>NeurokininB> B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, But the percentage of KNDy cells colocalizing progesterone receptors remained high in Both sexes. Prenatal T treatment also reduced the numBer of dynorphin, <B>NeurokininB> B, and progesterone receptor-positive cells in the female arcuate nucleus; however, the numBer of kisspeptin cells remained high and at levels comparaBle to control females. Thus, sex differences in kisspeptin in the arcuate nucleus, unlike that of dynorphin and <B>NeurokininB> B, are not due solely to exposure to prenatal T, suggesting the existence of different critical periods for multiple peptides coexpressed within the same neuron. In addition, the imBalance Between inhiBitory (dynorphin) and stimulatory (kisspeptin) neuropeptides in this suBpopulation provides a potential explanation for the decreased aBility of progesterone to inhiBit GnRH neurons in prenatal T-treated ewes.
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the kisspeptin <B>NeurokininB> B dynorphin kndy cell population of the arcuate nucleus sex differences and effects of prenatal testosterone in sheep
Endocrinology, 2010Co-Authors: Guanliang Cheng, Lique M. Coolen, Vasantha Padmanabhan, Robert L. Goodman, Michael N. LehmanAbstract:Recent work in sheep has identified a neuronal suBpopulation in the arcuate nucleus that coexpresses kisspeptin, <B>NeurokininB> B, and dynorphin (referred to here as KNDy cells) and that mediate the negative feedBack influence of progesterone on GnRH secretion. We hypothesized that sex differences in progesterone negative feedBack are due to sexual dimorphism of KNDy cells and compared neuropeptide and progesterone receptor immunoreactivity in this suBpopulation Between male and female sheep. In addition, Because sex differences in progesterone negative feedBack and <B>NeurokininB> B are due to the influence of testosterone (T) during fetal life, we determined whether prenatal T exposure would mimic sex differences in KNDy cells. Adult rams had nearly half the numBer of kisspeptin, <B>NeurokininB> B, dynorphin, and progesterone receptor-positive cells in the arcuate nucleus as did females, But the percentage of KNDy cells colocalizing progesterone receptors remained high in Both sexes. Prenatal T treatment also reduced...
G. Sperk - One of the best experts on this subject based on the ideXlab platform.
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somatostatin neuropeptide y <B>NeurokininB> B and cholecystokinin immunoreactivity in two chronic models of temporal loBe epilepsy
Neuroscience, 1995Co-Authors: Christoph Schwarzer, John Williamson, Eric W. Lothman, Annamaria Vezzani, G. SperkAbstract:Somatostatin-, neuropeptide Y-, <B>NeurokininB> B- and cholecystokinin-containing neurons were investigated in the rat hippocampus in two chronic models of temporal loBe epilepsy, i.e. 30 days after rapid kindling or electrically induced status epilepticus (post-status epilepticus). After rapid kindling, somatostatin immunoreactivity was strongly increased in interneurons and in the outer and middle molecular layer of the dentate gyrus. In four of six post-status epilepticus rats (status epilepticus I rats), somatostatin immunoreactivity was slightly increased in the dorsal But decreased in the ventral dentate gyrus and molecular layer. Somatostatin immunoreactivity decreased in neurons of the dorsal hilus in the two other post-status epilepticus rats investigated, while a complete loss was found in the respective ventral extension (status epilepticus-II rats). These changes were associated with a different extent of neurodegeneration as assessed By Nissl staining. Similarly, neuropeptide Y immunoreactivity was enhanced in neurons of the hilus and in the middle and outer molecular layer of the dentate gyrus in the dorsal hippocampus of rapidly kindled and status epilepticus-I rats. Neuropeptide Y and <B>NeurokininB> B immunoreactivity was enhanced in the mossy fiBers of all post-status epilepticus rats, But not in the rapidly kindled rats. In status epilepticus-II rats, neuropeptide Y-and <B>NeurokininB> B-positive fiBers were also detected in the infrapyramidal region of the stratum oriens of CA3 and in the inner molecular layer of the dentate gyrus in the dorsal and ventral hippocampus respectively, laBeling presumaBly sprouted mossy fiBers. Increased staining of neuropeptide Y and <B>NeurokininB> B was found in the alveus after rapid kindling. Cholecystokinin immunoreactivity was markedly increased in the cereBral cortex, Ammon's horn and the molecular layer of the dentate gyrus in the ventral hippocampus of rapidly kindled and post-status epilepticus rats. The lasting changes in the immunoreactive pattern of various peptides in the hippocampus may reflect functional modifications in the corresponding peptide-containing neurons. These changes may Be involved in chronic epileptogenesis, which evolves in response to limBic seizures.
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Somatostatin, neuropeptide Y, <B>NeurokininB> B and cholecystokinin immunoreactivity in two chronic models of temporal loBe epilepsy.
Neuroscience, 1995Co-Authors: Christoph Schwarzer, John Williamson, Eric W. Lothman, Annamaria Vezzani, G. SperkAbstract:ABstract Somatostatin-, neuropeptide Y-, <B>NeurokininB> B- and cholecystokinin-containing neurons were investigated in the rat hippocampus in two chronic models of temporal loBe epilepsy, i.e. 30 days after rapid kindling or electrically induced status epilepticus (post-status epilepticus). After rapid kindling, somatostatin immunoreactivity was strongly increased in interneurons and in the outer and middle molecular layer of the dentate gyrus. In four of six post-status epilepticus rats (status epilepticus I rats), somatostatin immunoreactivity was slightly increased in the dorsal But decreased in the ventral dentate gyrus and molecular layer. Somatostatin immunoreactivity decreased in neurons of the dorsal hilus in the two other post-status spilepticus rats investigated, while a complete loss was found in the respective ventral extension (status epilepticus-II rats). These changes were associated with a different extent of neurodegeneration as assessed By Nissl staining. Similarly, neuropeptide Y immunoreactivity was enhanced in neurons of the hilus and in the middle and outer molecular layer of the dentate gyrus in the dorsal hippocampus of rapidly kindled and status epilepticus-I rats. Neuropeptide Y and <B>NeurokininB> B immunoreactivity was enhanced in the mossy fiBers of all post-status epilepticus rats, But not in the rapidly kindled rats. In status epilepticus-II rats, neuropeptide Y-and <B>NeurokininB> B-positive fiBers were also detected in the infrapyramidal region of the stratum oriens of CA3 and in the inner molecular layer of the dentate gyrus in the dorsal and ventral hippocampus respectively, laBeling presumaBly sprouted mossy fiBers. Increased staining of neuropeptide Y and <B>NeurokininB> B was found in the alveus after rapid kindling. Cholecystokinin immunoreactivity was markedly increased in the cereBral cortex, Ammon's horn and the molecular layer of the dentate gyrus in the ventral hippocampus of rapidly kindled and post-status epilepticus rats. The lasting changes in the immunoreactive pattern of various peptides in the hippocampus may reflect functional modifications in the corresponding peptide-containing neurons. These changes may Be involved in chronic epileptogenesis, which evolves in response to limBic seizures.
Christopher E. Jones - One of the best experts on this subject based on the ideXlab platform.
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Copper ions trigger disassemBly of <B>NeurokininB> B functional amyloid and inhiBit de novo assemBly.
Journal of Structural Biology, 2019Co-Authors: Bhawantha M. Jayawardena, Mark R. Jones, Yuning Hong, Christopher E. JonesAbstract:ABstract The formation of amyloid is considered an intrinsic aBility of most polypeptides. It is a structure adopted By many neuropeptides and neurohormones during the formation of dense core vesicles in secretory cells, yet the mechanisms mediating assemBly and disassemBly of these amyloids remain unclear. <B>NeurokininB> B is a neuropeptide thought to form an amyloid in secretory cells. It is known to coordinate copper, But the physiological significance of metal Binding is not known. In this work we explored the amyloid formation of <B>NeurokininB> B and the impact that metals had on the aggregation Behaviour. We show that the production of <B>NeurokininB> B amyloid is dependent on the phosphate concentration, the pH and the presence of a histidine at position 3 in the primary sequence. Copper(II) and nickel(II) coordination to the peptide, which requires the histidine imidazole group, completely inhiBits amyloid formation, whereas zinc(II) slows, But does not inhiBit fiBrillogenesis. Furthermore, we show that copper(II) can rapidly disassemBle preformed <B>NeurokininB> B amyloid. This work identifies a role for copper in <B>NeurokininB> B structure and reveals a mechanism for amyloid assemBly and disassemBly dependent on metal coordination.
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<B>NeurokininB> B and serum alBumin limit copper Binding to mammalian gonadotropin releasing hormone.
Biochemical and Biophysical Research Communications, 2018Co-Authors: Ahmad Samir Gul, Kevin Tran, Christopher E. JonesAbstract:ABstract Gonadotropin releasing hormone (GnRH) triggers secretion of luteinizing hormone and follicle stimulating hormone from gonadotropic cells in the anterior pituitary gland. GnRH is aBle to Bind copper, and Both in vitro and in vivo studies have suggested that the copper-GnRH complex is more potent at triggering gonadotropin release than GnRH alone. However, it remains unclear whether copper-GnRH is the active species in vivo. To explore this we have estimated the GnRH-copper affinity and have examined whether GnRH remains copper-Bound in the presence of serum alBumin and the neuropeptide <B>NeurokininB> B, Both copper-Binding proteins that GnRH will encounter in vivo. We show that GnRH has a copper dissociation constant of ∼0.9 × 10−9 M, however serum alBumin and <B>NeurokininB> B can extract metal from the copper-GnRH complex. It is therefore unlikely that a copper-GnRH complex will survive transit through the pituitary portal circulation and that any effect of copper must occur outside the Bloodstream in the aBsence of <B>NeurokininB> B.
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The tachykinin peptide <B>NeurokininB> B Binds copper(I) and silver(I) and undergoes quasi-reversiBle electrochemistry: Towards a new function for the peptide in the Brain
Neurochemistry International, 2014Co-Authors: Aidan Bradley Grosas, Palraj Kalimuthu, Alison C. Smith, Peter A. Williams, Thomas J. Millar, Paul V. Bernhardt, Christopher E. JonesAbstract:The tachykinin neuropeptide family, which includes suBstance P and <B>NeurokininB> B, is involved in a wide array of Biological functions. Among these is the aBility to protect against the neurotoxic processes in Alzheimer's Disease, But the mechanisms driving neuroprotection remain unclear. Dysregulation of metal ions, particularly copper, iron and zinc is a common feature of Alzheimer's Disease, and other amyloidogenic disorders. Copper is known to Be released from neurons and recent work has shown that some tachykinins can Bind Cu(II) ions, and that <B>NeurokininB> B can inhiBit copper uptake into astrocytes. We have now examined whether <B>NeurokininB> B is capaBle of Binding Cu(I), which is predicted to Be availaBle in the synapse. Using a comBination of spectroscopic techniques including cyclic voltammetry and magnetic resonance we show that <B>NeurokininB> B can Bind Cu(I) either directly from added CuCl or By reduction of Cu(II)-Bound <B>NeurokininB> B. The results showed that the Cu(I) Binding site differs greatly to that of Cu(II) and involves thioether coordination via Met2 and Met10 and an imidazole nitrogen ligand from His3. The Cu(I) coordination is also different to the site adopted By Ag(I). During changes in oxidation state, copper remains Bound to <B>NeurokininB> B despite large changes to the inner coordination sphere. We predict that <B>NeurokininB> B may Be involved in synaptic copper homeostasis.
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The tachykinin peptide <B>NeurokininB> B Binds copper forming an unusual [CuII(NKB)2] complex and inhiBits copper uptake into 1321N1 astrocytoma cells
ACS chemical neuroscience, 2013Co-Authors: Debora Russino, Elle Mcdonald, Leila Hejazi, Graeme R. Hanson, Christopher E. JonesAbstract:<B>NeurokininB> B (NKB) is a memBer of the tachykinin family of neuropeptides that have neuroinflammatory, neuroimmunological, and neuroprotective functions. In a neuroprotective role, tachykinins can help protect cells against the neurotoxic processes oBserved in Alzheimer’s disease. A change in copper homeostasis is a clear feature of Alzheimer’s disease, and the dysregulation may Be a contriButory factor in toxicity. Copper has recently Been shown to interact with <B>NeurokininB> A and neuropeptide γ and can lead to generation of reactive oxygen species and peptide degradation, which suggests that copper may have a place in tachykinin function and potentially misfunction. To explore this, we have utilized a range of spectroscopic techniques to show that NKB, But not suBstance P, can Bind CuII in an unusual [CuII(NKB)2] neutral complex that utilizes two N-terminal amine and two imidazole nitrogen ligands (from each molecule of NKB) and the Binding suBstantially alters the structure of the peptide. Using 1321N1 astrocytoma cells, we show that copper can enter the cells and suBsequently open plasma memBrane calcium channels But when Bound to <B>NeurokininB> B copper ion uptake is inhiBited. This data suggests a novel role for <B>NeurokininB> B in protecting cells against copper-induced calcium changes and implicates the peptide in synaptic copper homeostasis.
Cintia Tusset - One of the best experts on this subject based on the ideXlab platform.
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tac3 tacr3 mutations reveal preferential activation of gonadotropin releasing hormone release By <B>NeurokininB> B in neonatal life followed By reversal in adulthood
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Elena Gianetti, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Sekoni D. Noel, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka B. Trarbach, Elaine M F CostaAbstract:Context: Mutations in TAC3 and TACR3 (encoding <B>NeurokininB> B and its receptor) have Been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), But Broader populations have not yet Been tested and genotype-phenotype correlations have not Been estaBlished. OBjective: A Broad cohort of normosmic IHH proBands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 proBands, 18 family memBers, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and Before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 proBands harBored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single Base pair deletion was identified, resulting in complete loss of the <B>NeurokininB> B decapeptide. Phenotypic information was availaBle on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversiBility of their hypogonadotropism. Conclusions: Mutations in the <B>NeurokininB> B pathway are relatively common as causes of hypogonadism. Although the <B>NeurokininB> B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
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TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release By <B>NeurokininB> B in Neonatal Life Followed By Reversal in Adulthood
The Journal of Clinical Endocrinology & Metabolism, 2010Co-Authors: Elena Gianetti, Cintia Tusset, Sekoni D. Noel, Andrew A. Dwyer, Virginia A. Hughes, Ana Paula Abreu, Jessica Carroll, Ericka B. Trarbach, Leticia Ferreira Gontijo SilveiraAbstract:Context: Mutations in TAC3 and TACR3 (encoding <B>NeurokininB> B and its receptor) have Been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), But Broader populations have not yet Been tested and genotype-phenotype correlations have not Been estaBlished. OBjective: A Broad cohort of normosmic IHH proBands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 proBands, 18 family memBers, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and Before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 proBands harBored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single Base pair deletion was identified, resulting in complete loss of the <B>NeurokininB> B decapeptide. Phenotypic information was availaBle on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversiBility of their hypogonadotropism. Conclusions: Mutations in the <B>NeurokininB> B pathway are relatively common as causes of hypogonadism. Although the <B>NeurokininB> B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
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Impact of mutations in kisspeptin and <B>NeurokininB> B signaling pathways on human reproduction.
Brain Research, 2010Co-Authors: Leticia Ferreira Gontijo Silveira, Cintia Tusset, Ana Claudia LatronicoAbstract:The involvement of kisspeptin and <B>NeurokininB> in B pathways in the reproductive axis was first suspected By linkage analysis in consanguineous families with isolated hypogonadotropic hypogonadism (IHH). Since then, several loss-of-function mutations affecting the kisspeptin receptor and <B>NeurokininB> B and its receptor were associated with sporadic and familial IHH without olfactory aBnormalities or other associated developmental alterations. Clinical manifestations were indistinguishaBle in individuals with mutations affecting these pathways. Micropenis and cryptorchidism were common findings among male patients. Response to acute GnRH stimulation varied from Blunted to normal, and many affected males and females were successfully treated for infertility with either exogenous gonadotropins or long term pulsatile GnRH infusion. More recently, rare activating mutations of the kisspeptin and its receptor were identified in children with idiopathic central precocious puBerty, supporting the crucial role of this system in the human puBertal onset. Kisspeptin is a potent excitatory regulator of the GnRH secretion, whereas the role of <B>NeurokininB> B in the neuroendocrine control of the reproductive axis is still poorly understood. Interestingly, kisspeptin and <B>NeurokininB> B are coexpressed in the arcuate nucleus in the mammalian hypothalamus, suggesting that these systems are closely related and potential partners of the regulation of the reproductive axis.