The Experts below are selected from a list of 708 Experts worldwide ranked by ideXlab platform
Ana Claudia Latronico - One of the best experts on this subject based on the ideXlab platform.
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molecular and genetic aspects of congenital Isolated Hypogonadotropic Hypogonadism
2017Co-Authors: Lorena Guimaraes Lima Amato, Ana Claudia Latronico, Leticia Ferreira Gontijo SilveiraAbstract:Congenital Isolated Hypogonadotropic Hypogonadism (IHH) is a clinically and genetically heterogenous disorder characterized by abnormal synthesis, secretion, or action of gonadotropin-releasing hormone, a key hypothalamic decapeptide that orchestrates the reproductive axis. Several modes of inheritance have been identified. A growing list of causative genes has been implicated in the molecular pathogenesis of syndromic and nonsyndromic IHH, largely contributing for better understanding the complex neuroendocrine control of reproduction. This article summarizes the great advances of molecular genetics of IHH and pointed up the heterogeneity and complexity of the genetic basis of this condition.
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novel mutation in the gonadotropin releasing hormone receptor gnrhr gene in a patient with normosmic Isolated Hypogonadotropic Hypogonadism
2012Co-Authors: Daiane Beneduzzi, Ana Claudia Latronico, Ericka B. Trarbach, Berenice B. Mendonca, Leticia Ferreira Gontijo SilveiraAbstract:We report a novel GNRHR mutation in a male with normosmic Isolated Hypogonadotropic Hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4
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clinical and molecular aspects of congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Cintia Tusset, Leticia Ferreira Gontijo Silveira, Daiane Beneduzzi, Ericka B. Trarbach, Luciana Ribeiro Montenegro, Ana Claudia LatronicoAbstract:Congenital Isolated Hypogonadotropic Hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH.
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Mutational analysis of the necdin gene in patients with congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Daiane Beneduzzi, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Pamela L. Mellon, Anita K. Iyer, Ericka B. Trarbach, A. P. Silveira-neto, Kathleen Yip, Berenice B. Mendonca, Ana Claudia LatronicoAbstract:Context: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the Hypogonadotropic Hypogonadism phenotype in patients with Prader‐Willi syndrome. Aim: To investigate necdin gene (NDN) variants in patients with Isolated Hypogonadotropic Hypogonadism (IHH). Patients and methods: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. Results: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. Conclusion: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the Hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.
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aspectos clinicos e moleculares do hipogonadismo hipogonadotrofico isolado congenito clinical and molecular aspects of congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Cintia Tusset, Daiane Beneduzzi, Ericka B. Trarbach, Luciana Ribeiro Montenegro, Leticia Ferreira, Gontijo Silveira, Ana Claudia LatronicoAbstract:SUMMARY Congenital Isolated Hypogonadotropic Hypogonadism (IHH) is characterized by partial or com-plete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anato-mical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mu-tations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11
Nicolas De Roux - One of the best experts on this subject based on the ideXlab platform.
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neuroendocrine phenotype analysis in five patients with Isolated Hypogonadotropic Hypogonadism due to a l102p inactivating mutation of gpr54
2007Co-Authors: Yardena Tenenbaumrakover, Nicolas De Roux, Monique Commengesducos, Andre Iovane, Chantal Aumas, Osnat AdmoniAbstract:Context: Loss of function of the G protein-coupled receptor of kisspeptins (GPR54) was recently described as a new cause of Isolated Hypogonadotropic Hypogonadism. In vivo studies performed in several species have confirmed the major role of kisspeptins in neuroendocrine regulation of the gonadotropic axis and therefore sexual maturation. Objective: The objective of this study was to specify the exact contribution of kisspeptins and GPR54 to the initiation of puberty in humans. Design: Detailed neuroendocrine descriptions were performed in five patients with Isolated Hypogonadotropic Hypogonadism bearing a new GPR54-inactivating mutation. Results: A homozygous mutation (T305C) leading to a leucine substitution with proline (L102P) was found in the five affected patients. This substitution completely inhibited GPR54 signaling. Phenotypic analysis revealed variable expressivity in the same family, either partial or complete gonadotropic deficiency. LH pulsatility analysis showed peaks with normal frequency ...
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Isolated Gonadotropic Deficiency with and without Anosmia: A Developmental Defect or a Neuroendocrine Regulation Abnormality of the Gonadotropic Axis
2005Co-Authors: Nicolas De RouxAbstract:Hypogonadotropic Hypogonadism has been described in several human genetic diseases. Congenital Isolated Hypogonadotropic Hypogonadism is classified into two categories: one that is associated with anosmia (Kallmann syndrome) and one that is apparently Isolated. Mutations and deletions of the KAL1 gene, which encodes for a protein involved in cell adhesion, have been observed in many cases of the X-linked form of Kallmann syndrome. Recently, loss-of-function mutations of fibroblast growth factor receptor-1 (FGFR1) were associated with an autosomal dominant form of Kallmann syndrome. Genotype-phenotype correlations confirm the large spectrum of the phenotype due to FGFR1 mutations. Cases of Isolated Hypogonadotropic Hypogonadism were considered to be idiopathic until the description of mutations of the gonadotropin releasing hormone receptor, luteinizing hormone and follicle stimulating hormone genes. However, defects in these genes only account for a small percentage of familial cases, which suggests that other proteins may be involved in regulation of the gonadotropic axis. We recently described GPR54 as one of these proteins by genome mapping in a very informative family. In vivo studies and genotype-phenotype correlations indicate that gonadotropic axis regulation by GPR54 occurs mainly at the level of the hypothalamus.
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molecular genetics of Isolated Hypogonadotropic Hypogonadism and kallmann syndrome
2005Co-Authors: Beate Karges, Nicolas De RouxAbstract:Isolated Hypogonadotropic Hypogonadism (IHH) is characterized by complete or partial failure of pubertal development due to impaired secretion of luteinizing hormone (LH) and follicle-stimulating ho
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new insights in the genetics of Isolated Hypogonadotropic Hypogonadism
2004Co-Authors: Andre Iovane, Chantal Aumas, Nicolas De RouxAbstract:Isolated gonadotropic deficiency or Isolated Hypogonadotropic Hypogonadism is defined as a low sexual hormone secretion by the gonads associated with low LH and FSH plasma levels. Kallmann syndrome is defined as a congenital Isolated gonadotropic deficiency associated with anosmia whereas the phenotype of the idiopathic form is limited to the gonadotropic axis. For several years, it has been known that mutations of the KAL-1 gene or loss-of-function mutations of GnRH receptor did not explain all familial cases of Isolated gonadotropic deficiency with or without anosmia. Thus the existence of other genes playing a major role in the physiology of the gonadotropic axis was highly suggested. In 2003, fibroblast growth factor receptor 1 (FGFR1) and GPR54 were shown to be two of these genes. FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.
Ericka B. Trarbach - One of the best experts on this subject based on the ideXlab platform.
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role of gonadotropin releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay
2014Co-Authors: Daiane Beneduzzi, Ericka B. Trarbach, Heraldo Mendes Garmes, Le Min, Alexander A L Jorge, Alessandra Covallero Renk, Marta Fichna, Piotr Fichna, Karina A Arantes, Elaine M F CostaAbstract:Objective To analyze the GNRHR in patients with normosmic Isolated Hypogonadotropic Hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). Design Molecular analysis and in vitro experiments correlated with phenotype. Setting Academic medical center. Patient(s) A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. Intervention(s) GNRHR coding region was amplified and sequenced. Main Outcome Measure(s) Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. Result(s) Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. Conclusion(s) GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.
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novel mutation in the gonadotropin releasing hormone receptor gnrhr gene in a patient with normosmic Isolated Hypogonadotropic Hypogonadism
2012Co-Authors: Daiane Beneduzzi, Ana Claudia Latronico, Ericka B. Trarbach, Berenice B. Mendonca, Leticia Ferreira Gontijo SilveiraAbstract:We report a novel GNRHR mutation in a male with normosmic Isolated Hypogonadotropic Hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4
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clinical and molecular aspects of congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Cintia Tusset, Leticia Ferreira Gontijo Silveira, Daiane Beneduzzi, Ericka B. Trarbach, Luciana Ribeiro Montenegro, Ana Claudia LatronicoAbstract:Congenital Isolated Hypogonadotropic Hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH.
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Mutational analysis of the necdin gene in patients with congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Daiane Beneduzzi, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Pamela L. Mellon, Anita K. Iyer, Ericka B. Trarbach, A. P. Silveira-neto, Kathleen Yip, Berenice B. Mendonca, Ana Claudia LatronicoAbstract:Context: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the Hypogonadotropic Hypogonadism phenotype in patients with Prader‐Willi syndrome. Aim: To investigate necdin gene (NDN) variants in patients with Isolated Hypogonadotropic Hypogonadism (IHH). Patients and methods: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. Results: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. Conclusion: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the Hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.
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aspectos clinicos e moleculares do hipogonadismo hipogonadotrofico isolado congenito clinical and molecular aspects of congenital Isolated Hypogonadotropic Hypogonadism
2011Co-Authors: Cintia Tusset, Daiane Beneduzzi, Ericka B. Trarbach, Luciana Ribeiro Montenegro, Leticia Ferreira, Gontijo Silveira, Ana Claudia LatronicoAbstract:SUMMARY Congenital Isolated Hypogonadotropic Hypogonadism (IHH) is characterized by partial or com-plete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anato-mical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mu-tations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11
Elaine M F Costa - One of the best experts on this subject based on the ideXlab platform.
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role of gonadotropin releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay
2014Co-Authors: Daiane Beneduzzi, Ericka B. Trarbach, Heraldo Mendes Garmes, Le Min, Alexander A L Jorge, Alessandra Covallero Renk, Marta Fichna, Piotr Fichna, Karina A Arantes, Elaine M F CostaAbstract:Objective To analyze the GNRHR in patients with normosmic Isolated Hypogonadotropic Hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). Design Molecular analysis and in vitro experiments correlated with phenotype. Setting Academic medical center. Patient(s) A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. Intervention(s) GNRHR coding region was amplified and sequenced. Main Outcome Measure(s) Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. Result(s) Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. Conclusion(s) GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.
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a novel homozygous splice acceptor site mutation of kiss1r in two siblings with normosmic Isolated Hypogonadotropic Hypogonadism
2010Co-Authors: Milena Gurgel Teles, Daiane Beneduzzi, Ericka B. Trarbach, Alexander A L Jorge, S D Noel, Gil Guerrajunior, Suzy D C Bianco, A Mukherjee, M T M Baptista, Elaine M F CostaAbstract:Context: Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic Isolated Hypogonadotropic Hypogonadism (nIHH). Objective: To investigate KISS1R defects in patients with absent or delayed puberty. Patients: We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP). Methods: The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification. Results: One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position K 2t oK4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3 0 splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP. Conclusion: Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.
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novel fibroblast growth factor receptor 1 mutations in patients with congenital Hypogonadotropic Hypogonadism with and without anosmia
2006Co-Authors: Ericka B. Trarbach, Berenice B. Mendonca, Elaine M F Costa, Beatriz R Versiani, Margaret De Castro, Maria Tereza Matias Baptista, Heraldo Mendes Garmes, Ana Claudia LatronicoAbstract:Context: Kallmann syndrome is a clinically and genetically heterogeneous disorder. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. Objective: The objective was to investigate genetic defects in the KAL1 and FGFR1 genes in patients with congenital Isolated Hypogonadotropic Hypogonadism (IHH). Patients: Eighty patients (71 males and nine females) with IHH were studied, of which 30 were familial. Forty-six of them had olfactory abnormalities. Methods: The coding regions of both KAL1 and FGFR1 genes were amplified and automatically sequenced. The KAL1 mutations were investigated only in patients with olfactory abnormalities, whereas FGFR1 was studied in the entire group. Results: Two novel KAL1 mutations, an intragenic deletion of exons 3–6 and a splicing mutation IVS7 + 1G>A, were identified in two of 46 patients with Kallmann syndrome. Ei...
Jihong Liu - One of the best experts on this subject based on the ideXlab platform.
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an Isolated Hypogonadotropic Hypogonadism male with a novel de novofgfr1 mutation fathered a normal son evidenced by prenatal genetic diagnosis
2020Co-Authors: Taotao Sun, Shaogang Wang, Tao Wang, Yingwei Chen, Daoqi Wang, Jihong LiuAbstract:Isolated Hypogonadotropic Hypogonadism (IHH) is a rare but treatable form of male infertility caused by congenital defect in gonadotropin-releasing hormone (GnRH) secretion or action. We report a Chinese IHH male with a novel FGFR1 mutation who successfully fathered a normal son. Targeted next-generation sequencing, bioinformatics analysis and Sanger sequencing were performed by using the DNA extracted from the pedigree. The patient was treated with gonadotropin and was able to impregnant his wife during the treatment. Amniocentesis was performed at the 18 weeks of gestation. A novel de novo pathogenic missense variant (c.980A>G, p.Asn327Ser) in exon 8 in FGFR1 gene (NM_001174067.1) was identified in the patient but not in his normal parents. This variant was also absent in the DNA obtained from the amniocentesis sample. His son has normal growth and development at the age of 2 years. This is the first case of prenatal genetic diagnosis based on the genetic testing of the IHH father by combining targeted next-generation and Sanger sequencing in IHH family. We extended the mutation spectrum of FGFR1 in IHH patients. Prenatal genetic diagnosis based on the results of genetic testing of the IHH patients may be helpful in the genetic counselling for the IHH families.
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testosterone undecanoate supplementation together with human chorionic gonadotropin does not impair spermatogenesis in males with Isolated Hypogonadotropic Hypogonadism a retrospective study
2019Co-Authors: Yinwei Chen, Yonghua Niu, Shaogang Wang, Tao Wang, Daoqi Wang, Hongyang Jiang, Gaurab Pokhrel, Jihong LiuAbstract:Gonadotropin therapy is commonly used to induce virilization and spermatogenesis in male Isolated Hypogonadotropic Hypogonadism (IHH) patients. In clinical practice, 5.6%-15.0% of male IHH patients show poor responses to gonadotropin treatment; therefore, testosterone (T) supplementation can serve as an alternative therapy to normalize serum T levels and promote virilization. However, treatment with exogenous T impairs spermatogenesis and suppresses intratesticular T levels. This retrospective study aimed to determine whether oral testosterone undecanoate (TU) supplementation together with human chorionic gonadotropin (hCG) would negatively affect spermatogenesis in IHH patients compared with hCG alone. One hundred and seven IHH patients were included in our study. Fifty-four patients received intramuscular hCG and oral TU, and 53 patients received intramuscular hCG alone. The median follow-up time was 29 (range: 12-72) months in both groups. Compared with the hCG group, the hCG/TU group required a shorter median time to normalize serum T levels (P < 0.001) and achieve Tanner stage (III and V) of pubic hair and genital development (P < 0.05). However, there were no significant differences in the rate of seminal spermatozoa appearance, sperm concentration, or median time to achieve different sperm concentration thresholds between the groups. In addition, there were no significant differences in side effects, such as acne and gynecomastia, observed in both groups. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated IHH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.
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mutation profiles and clinical characteristics of chinese males with Isolated Hypogonadotropic Hypogonadism
2018Co-Authors: Chengming Zhou, Yonghua Niu, Shaogang Wang, Tao Wang, Weimin Yang, Dao Wen Wang, Jihong LiuAbstract:Objective To investigate the mutation profiles and clinical characteristics of Chinese males with Isolated Hypogonadotropic Hypogonadism (IHH) and discover new pathogenic genes that cause IHH. Design A gene panel, including 31 known IHH genes and 52 candidate genes, was used to perform semiconductor next-generation sequencing. Setting University hospital. Patients One hundred thirty-eight sporadic male IHH patients and 10 IHH families; 100 healthy men with normal fertility served as control subjects. Interventions(s) None. Main Outcome Measure(s) Targeted next-generation sequencing, polymerase chain reaction and sequencing, pedigree analysis, and bioinformatics analysis. Result(s) Variants were distributed uniformly throughout 52 genes (52/83, 62.65%), including 16 (16/31, 51.61%) causal genes and 36 (36/52, 69.23%) candidate genes. Six new pathogenic variants and 52 likely pathogenic variants were identified in 16 genes known to cause nIHH/KS (normosmic IHH/Kallmann syndrome). In the 148 probands, PROKR2 (22/148, 14.86%), CHD7, FGFR1, and KAL1 had high mutation rates, and 8.78% (13/148) of the patients carried at least two variants in known genes. In addition, variants were identified in 36 candidate genes, and EGFR, ERBB4, PAX6, IGF1, SEMA4D, and SEMA7A should be prioritized for further research and genetic testing in IHH. Conclusion(s) The mutation frequency of IHH-causal genes in Chinese HAN males was different from the data reported in white populations. Oligogenic inheritance was a common phenomenon in IHH. Our study expands the mutation profile for IHH, and the new likely pathogenic genes identified in our study warrant further research in GnRH neuronal networks.
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Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate
2015Co-Authors: Yonghua Niu, Simi Liu, Shaogang Wang, Jihong LiuAbstract:Kallmann syndrome (KS) is characterized by Isolated Hypogonadotropic Hypogonadism (IHH) with anosmia and is sometimes associated with cleft lip/palate (CLP). In order to describe the clinical features, genetic etiology, and treatment outcome of KS males with CLP, we performed genetic screening for 15 known causal IHH genes (KAL1, FGFR1, NELF, FGF8, CHD7, WDR11, SEMA3A, KISS1R, KISS1, PROKR2, PROK2, TAC3, TACR3, GNRH1, and GNRHR) in four KS with CLP patients and six IHH patients without CLP. Two novel heterozygous missense mutations in FGFR1, (NM_001174066): c.776G>A (p.G259E) and (NM_001174066): c.358C>T (p.R120C), were identified in a 23-year-old KS male with cleft lip and an 18-year-old KS patient with cleft lip and palate, dental agenesis, and high arched palate, respectively. These two mutations were not presented in their healthy parents and 200 normal controls. One novel heterozygous missense mutation in KISS1R, (NM_032551): c.587C>A (p.P196H), was identified in an 18-year-old KS male with cleft lip and dental agenesis who developed sperm after being treated with gonadotropin. This mutation was also presented in his healthy father and grandfather. These results have implications for the diagnosis, genetic counseling, and treatment of KS and CLP males with mutations in FGFR1 gene
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Research Article Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate
2015Co-Authors: Yonghua Niu, Simi Liu, Shaogang Wang, Jihong LiuAbstract:permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kallmann syndrome (KS) is characterized by Isolated Hypogonadotropic Hypogonadism (IHH) with anosmia and is sometimes associated with cleft lip/palate (CLP). In order to describe the clinical features, genetic etiology, and treatment outcome of KS males with CLP, we performed genetic screening for 15 known causal IHH genes (KAL1, FGFR1, NELF, FGF8, CHD7, WDR11, SEMA3A,KISS1R,KISS1,PROKR2,PROK2,TAC3,TACR3,GNRH1, andGNRHR) in fourKSwithCLPpatients and six IHHpatients without CLP. Two novel heterozygous missensemutations in FGFR1, (NM 001174066): c.776G>A (p.G259E) and (NM 001174066): c.358C>T (p.R120C), were identified in a 23-year-old KS male with cleft lip and an 18-year-old KS patient with cleft lip and palate, dental agenesis, and high arched palate, respectively. These two mutations were not presented in their healthy parents and 200 normal controls. One novel heterozygous missense mutation in KISS1R, (NM 032551): c.587C>A (p.P196H), was identified in an 18-year-old KS male with cleft lip and dental agenesis who developed sperm after being treated with gonadotropin. This mutation was also presented in his healthy father and grandfather. These results have implications for the diagnosis, genetic counseling, and treatment of KS and CLP males with mutations in FGFR1 gene. 1
