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Catherine Dode - One of the best experts on this subject based on the ideXlab platform.
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prok2 prokr2 signaling and Kallmann Syndrome
Frontiers in Endocrinology, 2013Co-Authors: Catherine Dode, Philippe RondardAbstract:Kallmann Syndrome (KS) is a developmental disease that associates hypogonadism and a deficiency of the sense of smell. The reproductive phenotype of KS results from the primary interruption of the olfactory, vomeronasal and terminal nerve fibers in the frontonasal region, which in turn disrupts the embryonic migration of neuroendocrine gonadotropin-releasing hormone (GnRH) synthesizing cells from the nose to the brain. This is a highly heterogeneous genetic disease, and mutations in any of the nine genes identified so far have been found in approximately 30% of the KS patients. PROKR2 and PROK2, which encode the G protein-coupled prokineticin receptor-2 and its ligand prokineticin-2, respectively, are two of these genes. Homozygous knockout mice for the orthologous genes exhibit a phenotype reminiscent of the KS features, but biallelic mutations in PROKR2 or PROK2 (autosomal recessive mode of disease transmission) have been found only in a minority of the patients, whereas most patients carrying mutations in these genes are heterozygotes. The mutations, mainly missense mutations, have deleterious effects on PROKR2-signaling in transfected cells, ranging from defective cell surface-targeting of the receptor to defective coupling to G-proteins or impaired receptor-ligand interaction, but the same mutations have also been found in apparently unaffected individuals, which suggests a digenic/oligogenic mode of inheritance of the disease in heterozygous patients. This non-Mendelian mode of inheritance has so far been confirmed only in a few patients. However, it may account for the unusually high proportion of KS sporadic cases compared to familial cases.
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Kallmann Syndrome
European Journal of Human Genetics, 2009Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:The Kallmann Syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2 , encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.
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biallelic mutations in the prokineticin 2 gene in two sporadic cases of Kallmann Syndrome
European Journal of Human Genetics, 2008Co-Authors: Chrystel Leroy, Jean-pierre Hardelin, Corinne Fouveaut, Sandrine Leclercq, Sebastien Jacquemont, Helene Du Boullay, James Lespinasse, Marc Delpech, Jeanmichel Dupont, Catherine DodeAbstract:Kallmann Syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann Syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann Syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann Syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann Syndrome genes.
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Kallmann Syndrome mutations in the genes encoding prokineticin 2 and prokineticin receptor 2
PLOS Genetics, 2005Co-Authors: Catherine Dode, Jacqueline Levilliers, Corinne Fouveaut, James Lespinasse, Luis Teixeira, Philippe Bouchard, Marie Laure Kottler, Anne Lienhardtroussie, M Mathieu, Alexandre MoermanAbstract:Kallmann Syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann Syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann Syndrome.
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Kallmann Syndrome: fibroblast growth factor signaling insufficiency?
Journal of Molecular Medicine, 2004Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:Kallmann Syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approx. 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann Syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
Jiada Li - One of the best experts on this subject based on the ideXlab platform.
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a dominant negative fgfr1 mutation identified in a Kallmann Syndrome patient
Gene, 2017Co-Authors: Ruizhi Zheng, Danna Chen, Jiada Li, Yaguang Zhao, Jiayu Wu, Jie Li, Fang Jiang, Xiaotao ZhouAbstract:Abstract Kallmann Syndrome (KS) is characterized by isolated hypogonadotropic hypogonadism (IHH) with anosmia. Fibroblast growth factor receptor 1 (FGFR1) is one of KS-associated genes, accounts for approximately 10% of total patients. FGFR1 mutations have also been identified in more severe craniosynostosis Syndromes, and a subset of craniosynostosis Syndromes-associated FGFR1 mutations show dominant negative effect. In this study, we identified a novel FGFR1 mutation (c.867G > A; p.W289X) in a KS patient. The p.W289X mutation leads premature termination, producing a truncated FGFR1 without the transmembrane and intracellular domains. Indeed, the W289X FGFR1 was secreted into culture medium. Further, W289X FGFR1 interfered with the function of wild type receptor to induce ERK1/2 phosphorylation. We therefore identified a dominant negative FGFR1 mutation in the KS patient, and this mutant FGFR1 may be used to decipher the physiological function of FGFR1.
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functional rescue of Kallmann Syndrome associated prokineticin receptor 2 pkr2 mutants deficient in trafficking
Journal of Biological Chemistry, 2014Co-Authors: Danna Chen, Qunyong Zhou, Jiada LiAbstract:Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann Syndrome and idiopathic hypogonadotropic hypogonadism manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface; instead, they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Here, we chose three disease-associated mutations (W178S, G234D, and P290S), which all resulted in retention of PKR2 intracellularly. We show that a small molecule PKR2 antagonist (A457) dramatically increased cell surface expression and rescued the function of P290S PKR2, but had no effect on W178S and G234D PKR2. Furthermore, we also tested chemical chaperone glycerol on the cell surface expression and function of PKR2 mutants. Treatment with 10% glycerol significantly increased the cell surface expression and signaling of P290S and W178S PKR2. These data demonstrate that some Kallmann Syndrome-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations.
Jean-pierre Hardelin - One of the best experts on this subject based on the ideXlab platform.
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Kallmann Syndrome
European Journal of Human Genetics, 2009Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:The Kallmann Syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2 , encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.
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biallelic mutations in the prokineticin 2 gene in two sporadic cases of Kallmann Syndrome
European Journal of Human Genetics, 2008Co-Authors: Chrystel Leroy, Jean-pierre Hardelin, Corinne Fouveaut, Sandrine Leclercq, Sebastien Jacquemont, Helene Du Boullay, James Lespinasse, Marc Delpech, Jeanmichel Dupont, Catherine DodeAbstract:Kallmann Syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann Syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann Syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann Syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann Syndrome genes.
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Kallmann Syndrome: fibroblast growth factor signaling insufficiency?
Journal of Molecular Medicine, 2004Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:Kallmann Syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approx. 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann Syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
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Kallmann Syndrome towards molecular pathogenesis
Molecular and Cellular Endocrinology, 2001Co-Authors: Jean-pierre HardelinAbstract:Abstract Gonadotropin Releasing Hormone (GnRH) is a key regulator of reproduction and sexual behaviour. During the last decade, embryological studies have clarified the question of the early development of GnRH-synthesising neurones before the onset of neurosecretion. These studies have revealed the existence of a topographical link between GnRH-synthesising neurones and the embryonic olfactory system, thereby shedding new light on Kallmann Syndrome, a developmental disease characterised by the association of hypogonadotropic hypogonadism and anosmia (or hyposmia). Although Kallmann Syndrome was identified as an inherited disease in the forties, familial cases of the disease are infrequent. However, the identification, by positional cloning strategies, of the gene underlying the X-chromosome linked form of the disease (KAL-1) has opened the way to molecular pathophysiology. KAL-1 encodes an extracellular glycoprotein of compound modular structure. The protein, named anosmin-1, has been produced in a transfected mammalian cell line and purified. Polyclonal and monoclonal antibodies have been generated, which allowed us to study the distribution of the protein during the period of human organogenesis (4–10 embryonic weeks), by immunohistofluorescence. During this developmental period, anosmin-1 is a locally restricted component of various extracellular matrices (interstitial matrices and basement membranes). Later in embryonic life, KAL-1 expression apparently becomes restricted to definite neuronal populations. Based on the distribution of anosmin-1 in the early olfactory system, the pathogenesis of the olfactory loss and GnRH deficiency in X-linked Kallmann Syndrome is discussed.
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heterogeneity in the mutations responsible for x chromosome linked Kallmann Syndrome
Human Molecular Genetics, 1993Co-Authors: Jean-pierre Hardelin, Pierre Bouloux, Jacqueline Levilliers, Stephane Blanchard, Jeanclaude Carel, Marc Leutenegger, Jeanpierre Pinardbertelletto, Christine PetitAbstract:Abstract Kallmann Syndrome represents the association of hypogonadotropic hypogonadism with anosmia. Three modes of transmission, X chromosome-linked, autosomal recessive and autosomal dominant, have been described. The KAL gene, responsible for the X-linked form of the disease, has been isolated and its intron-exon organization recently determined. We have searched for mutations of the KAL gene in 21 unrelated males affected by familial Kallmann Syndrome. In these families, segregation of the disease was suggestive of the X-linked mode of transmission. In 2 families, large Xp22.3 deletions, both including the entire KAL gene, have been detected by Southern blot analysis. Here we report the sequence analysis of the entire coding region of the KAL gene in the 19 remaining patients. The approach consisted of sequencing each of the 14 coding exons and splice site junctions. Each exon was amplified by PCR on the genomic DNA, using oligonucleotides from the flanking intronic sequences as specific primers. Nine point mutations were identified at separate locations in four exons and one splice site, providing strong evidence for heterogeneity in mutations responsible for the X-linked Kallmann Syndrome. In addition, the high frequency of unilateral renal aplasia in X-linked Kallmann patients (6 out of 11 males with identified alterations of the KAL gene) should be emphasized.
Johanna Tommiska - One of the best experts on this subject based on the ideXlab platform.
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prokr2 mutations in autosomal recessive Kallmann Syndrome
Fertility and Sterility, 2013Co-Authors: Johanna Tommiska, Jorma Toppari, Kirsi Vaaralahti, Johanna Kansakoski, Eevamaria Laitinen, Parinya Noisa, Anne KinnalaAbstract:Objective To investigate the inheritance pattern of two missense PROKR2 changes within a single family. Design This is a descriptive study. Setting Tertiary referral center. Patient(s) The proband and his brother, both with congenital hypogonadotropic hypogonadism and anosmia (Kallmann Syndrome). Intervention(s) Clinical and biochemical evaluation of Kallmann Syndrome. Sequence analysis of the coding exons and exon-intron boundaries of KAL1 , FGFR1 , FGF8 , PROK2 , and PROKR2 from polymerase chain reaction (PCR)-amplified genomic DNA. Recombinant human FSH treatment of the proband. Main Outcome Measure(s) Phenotypic and genotypic features, and inhibin B response to recombinant human FSH. Result(s) The proband and his brother were homozygous for two variants in PROKR2 ; a novel mutation c.701G>A (p.G234D), and a polymorphism c.802C>T (p.R268C). Recombinant human FSH therapy of the proband increased serum inhibin B from Conclusion(s) These findings are consistent with recessive mode of inheritance. PROKR2 signaling does not directly affect Sertoli cell function.
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genetic overlap between holoprosencephaly and Kallmann Syndrome
Molecular Syndromology, 2012Co-Authors: Kirsi Vaaralahti, Eevamaria Laitinen, Taneli Raivio, Rosanna Koivu, Leena Valanne, Johanna TommiskaAbstract:Patients with Kallmann Syndrome (KS; congenital hypogonadotropic hypogonadism and decreased/absent sense of smell), septo-optic dysplasia (SOD), or holoprosencephaly (HPE) reportedly have midline defects. In this study, we investigate a genetic overlap between KS, SOD, and HPE. Nineteen subjects (18 males, 1 female) with KS and without mutations in the known KS genes were screened for mutations in SOX2, SHH, SIX3,TGIF1,TDGF1,FOXH1,GLI2, and GLI3. One male carried 2 heterozygous missense changes, one in SIX3 (c.428G>A, p.G143D) and the other in GLI2 (c.2509G>A, p.E837K). Both of these genes have been implicated in the etiology of HPE and neither of these changes were present in 200 control subjects. Other variants found among the subjects were known polymorphisms. KS and HPE may display a genetic overlap. The involvement of genes implicated in the etiology of midline defects in patients with KS warrants further studies.
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genetic overlap in Kallmann Syndrome combined pituitary hormone deficiency and septo optic dysplasia
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Taneli Raivio, Johanna Tommiska, Andrew A Dwyer, Magdalena Avbelj, Mark J Mccabe, Christopher J Romero, Gerasimos P Sykiotis, Louise C Gregory, Daniel Diaczok, Vaitsa TziaferiAbstract:Context: Kallmann Syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in P...
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incidence phenotypic features and molecular genetics of Kallmann Syndrome in finland
Orphanet Journal of Rare Diseases, 2011Co-Authors: Johanna Tommiska, Kirsi Vaaralahti, Eevamaria Laitinen, Leena Valanne, Elina Eklund, Mari H Tervaniemi, Taneli RaivioAbstract:Background: Kallmann Syndrome (KS), comprised of congenital hypogonadotropic hypogonadism (HH) and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients. Methods: Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland. Results: The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000) and females (1:125 000) (p = 0.02). The reproductive phenotype of 30 probands (25 men; 5 women) ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes. Conclusions: Our results suggest that Finnish KS men harbor mutations in gene(s) yet-to-be discovered with sexdependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-Syndrome associated phenotypic features (e.g. ear or eye anomalies), possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.
Margaret De Castro - One of the best experts on this subject based on the ideXlab platform.
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combined use of multiplex ligation dependent probe amplification and automatic sequencing for identification of kal1 defects in patients with Kallmann Syndrome
Fertility and Sterility, 2013Co-Authors: Luciana Ribeiro Montenegro, Margaret De Castro, Beatriz R Versiani, Berenice B Mendonca, Ana Claudia Latronico, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Ericka B TrarbachAbstract:Objective To investigate the role of KAL1 abnormalities in Brazilian patients with Kallmann Syndrome. Design In vitro experiments. Setting Academic medical center. Patient(s) One hundred fifteen Brazilian patients (98 men) with Kallmann Syndrome. Intervention(s) Peripheral blood leukocytes were used to obtain DNA. Main Outcome Measure(s) Direct sequencing and multiplex ligation-dependent probe amplification were used to identify KAL1 abnormalities. Result(s) We identified four KAL1 mutations (p.Met1?, p.Ala33Glyfs, p.Arg257*, and p.Trp462*) and two multiple exon deletions (exons 1–2 and 3–14) in six new male patients. Overall, 17 KAL1 defects (14.8%) were identified in the entire cohort of patients with Kallmann Syndrome, including previously studied cases. KAL1- mutated patients presented with a more severe reproductive and nonreproductive phenotype (synkinesia, renal malformations, cryptorchidism, and anatomic olfactory abnormalities) in comparison with patients without KAL1 mutations. Intragenic deletions were one of the most often encountered defects (29.4%). These deletions can be missed by polymerase chain reaction (PCR) due to Yq11.2 KAL1 pseudogene ( KALP) spurious amplification. Conclusion(s) These results indicate that intragenic multiexon deletions are one of the most frequent KAL1 abnormalities, which can be more accurately detected by multiplex ligation-dependent probe amplification. In addition, KAL1 sequencing results should be interpreted with caution, and stringency conditions of the PCR reaction should be adjusted to avoid pseudogene amplification.
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quantitative magnetic resonance imaging evaluation of the olfactory system in Kallmann Syndrome correlation with a clinical smell test
Neuroendocrinology, 2011Co-Authors: Marcel Koenigkamsantos, Beatriz R Versiani, Antonio Carlos Dos Santos, Paula Rejane Beserra Diniz, Jorge Elias, Margaret De CastroAbstract:Objectives: To measure olfactory bulbs and sulci using dedicated magnetic resonance imaging (MRI) sequences and specific measurement tools in Kallmann Syndrome (KS) patients with a
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loss of function mutations in the genes encoding prokineticin 2 or prokineticin receptor 2 cause autosomal recessive Kallmann Syndrome
The Journal of Clinical Endocrinology and Metabolism, 2008Co-Authors: Ana Paula Abreu, Ericka B Trarbach, Margaret De Castro, Elaine M F Costa, Beatriz R Versiani, Maria Tereza Matias Baptista, Heraldo Mendes Garmes, Berenice B Mendonca, Ana Claudia LatronicoAbstract:Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice. Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities. Design: We studied 107 Brazilian patients with HH (63 with Kallmann Syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing. Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann Syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann Syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C miss...