Publications (10)26.65 Total impact
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Article: Genetic analysis in patients with Kallmann syndrome: coexistence of mutations in prokineticin receptor 2 and KAL1.
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ABSTRACT: Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. To date, 4 different genes have been identified as responsible for the presence of KS; however, in many cases no mutations have been found in any of these genes. Herein, we report the molecular findings regarding the analysis of fibroblast growth factor receptor 1 (FGFR1), prokineticin receptor 2 (PROKR2), and prokineticin (PROK2) in patients with KS. Twenty-four patients with KS were studied in whom mutations in KAL1 had been investigated previously. Polymerase chain reaction products from FGFR1, PROKR2, and PROK2 were sequenced and mutations were sought in the open reading frame of the 3 genes. Two patients presented a heterozygous T-to-G transversion in exon 2 (c.518T>G) of the PROKR2, which results in a leucine-to-arginine substitution at codon 173. Our results strengthen the hypothesis of possible digenic inheritance in some patients with KS. Likewise, our data extend previous reports demonstrating that PROKR2 plays a role in the etiology of this syndrome.Journal of Andrology 09/2008; 30(1):41-5. · 2.97 Impact Factor -
Article: In vitro biological-to-immunological ratio of serum gonadotropins throughout male puberty in children with insulin-dependent diabetes mellitus.
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ABSTRACT: Information on the impact of prolonged deficient glycemic control in the quality of the gonadotropin signal delivered by the pituitary gland during puberty in children with insulin-dependent diabetes mellitus (IDDM) is scarce. In the present study, we examined the impact of deficient glycemic control on bioactive LH and FSH concentrations and their corresponding biological-to-immunological (B:I) ratio in boys with poorly controlled, but systemically uncomplicated IDDM. Dual control groups comprising patients with well-controlled IDDM and healthy boys of comparable age and body mass index were included for appropriate comparisons within and between each pubertal stage. Patients with poorly controlled and well-controlled IDDM exhibited serum bioactive FSH levels and B:I FSH ratio similar to those showed by the healthy control group. In contrast, in early and mid-pubertal boys with poorly controlled IDDM bioactive LH levels were normal, but its B:I LH relationship was significantly (P < 0.05) decreased. This attenuation in the quality of the LH signal did not affect total serum T concentrations, and apparently, progression of puberty. Long-standing uncontrolled diabetes and the consequent metabolic disturbances and/or complications may aggravate the reproductive axis dysfunction and eventually provoke pubertal arrest.Endocrine 03/2007; 31(1):18-26. · 1.42 Impact Factor -
Article: Mutation analysis of the WNT-4 gene in patients with polycystic ovary syndrome.
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ABSTRACT: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women of childbearing age and is characterized by chronic anovulation with either oligomenorrhea or amenorrhea and hyperandrogenism. The etiology of this entity remains unknown. It has been suggested that genomic variants in genes related to the regulation of androgen biosynthesis and function could be involved in genetic predisposition to PCOS. WNT-4 is a member of the WNT family of secreted molecules. Studies on female Wnt-4 knockout mice have suggested that this gene suppresses gonadal androgen synthesis in normal females. We investigated if 25 women with PCOS presented mutations in WNT-4 as the cause of their disorder. Direct sequencing of all five exons demonstrated no mutant alleles in any patient. This study demonstrates that, at least in the population studied, mutations of the open reading frame of WNT-4 gene or its intron/exon junctions are not the cause of PCOS. However, the present data do not rule out the possible existence of causative mutations in the WNT-4 gene promoter region.Gynecological Endocrinology 10/2006; 22(9):484-7. · 1.58 Impact Factor -
Article: Screening for mutations in the WNT-4 gene in patients with 46,XX true hermaphroditism.
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ABSTRACT: We investigated if eight SRY-negative 46,XX true hermaphrodites presented mutations in WNT-4, in blood leukocytes and/or gonadal tissue, as the cause of their disorder. We designed the sequences of the reverse primer of exon 1 and the primers of exons 2-5. Direct sequencing of all five exons demonstrated no mutant alleles in any of the patients. The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out.Molecular Genetics and Metabolism 01/2005; 83(4):341-3. · 3.19 Impact Factor -
Article: Screening for mutations in the SRY gene in patients with mixed gonadal dysgenesis or with Turner syndrome and Y mosaicism.
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ABSTRACT: To investigate the presence of mutations in the open reading frame (ORF), as well as on the 5' and 3', flanking regions of the SRY gene in patients with mixed gonadal dysgenesis (MGD) or with Turner syndrome (TS) and Y mosaicism. We studied 13 patients with MGD and three patients with TS and Y mosaicism. DNA was isolated from blood leukocytes for subsequent polymerase chain reaction (PCR) and direct sequencing were performed in the ORF, as well as from the 5' and 3' flanking regions of the SRY gene. No mutations were present in any of the patients studied. The absence of mutations in these regions indicated that mutations were an unlikely cause of MGD or TS with Y mosaicism and suggested that there are others genes playing an important role in sex development.European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2004; 115(1):55-8. · 1.97 Impact Factor -
Article: Gonadoblastoma in Turner syndrome patients with nonmosaic 45,X karyotype and Y chromosome sequences.
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ABSTRACT: Turner syndrome (TS) is a disorder caused by partial or complete X-chromosome monosomy. Studies in TS patients with different karyotypes have demonstrated the presence of Y-chromosome-derived sequences (4-61%). Early detection of Y-chromosome sequences in TS is of great importance because of the high risk of gonadal tumor development. We investigated the presence of Y-chromosome sequences in TS patients with a 45,X karyotype. One hundred seven unrelated 45,X Mexican TS patients recruited between 1992 and 2003 were included. Y-chromosome-derived sequences were found by polymerase chain reaction in 10 (9.3%) patients. Six subjects underwent gonadectomy and in one of them a gonadoblastoma was found; another developed a gonadoblastoma with dysgerminoma. Because of the high proportion (33%) of gonadal tumors in patients with Y-chromosome sequences found among our patients of mestizo origin, adequate counseling regarding a gonadectomy should be given.Cancer Genetics and Cytogenetics 05/2004; 150(1):70-2. · 1.39 Impact Factor -
Article: Screening for mutations in the WNT4 gene in patients with 46,XX true hermaphroditism
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ABSTRACT: We investigated if eight SRY-negative 46,XX true hermaphrodites presented mutations in WNT-4, in blood leukocytes and/or gonadal tissue, as the cause of their disorder. We designed the sequences of the reverse primer of exon 1 and the primers of exons 2–5. Direct sequencing of all five exons demonstrated no mutant alleles in any of the patients. The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out.Molecular Genetics and Metabolism - MOL GENET METAB. 01/2004; 83(4):341-343. -
Article: A novel mutation of the insulin-like 3 gene in patients with cryptorchidism.
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ABSTRACT: Two independent studies demonstrated that transgenic mice with a targeted deletion of the insulin-like 3 ( INSL3) gene presented bilateral cryptorchidism. Studies in humans have investigated the possibility that mutations in the INSL3 gene are the cause of cryptorchidism. In the present study, genomic DNA was obtained from 150 patients with idiopathic cryptorchidism. DNA was amplified and the polymerase chain reaction products of both exons were sequenced. A previously unidentified missense mutation was found in only one of the patients studied. In exon 2, a heterozygous C/G substitution at nucleotide 2560, which turned asparagine into lysine at codon 86, was documented. The familial study revealed that the mother was a heterozygous carrier of the mutation and the father was a homozygote wild type. We also found three polymorphic changes, previously reported in exon 1. The Asn-into-Lys change is likely deleterious because it leads to a nonconservative amino acid substitution, changing a highly conserved residue. This mutation, located in the A-chain of the INSL3 protein, is the first mutation reported in this region. This finding provides new evidence that INSL3 is involved in testicular descent in humans; however, mutations of this gene are not a frequent cause of cryptorchidism.Journal of Human Genetics 02/2003; 48(2):86-90. · 2.57 Impact Factor -
Article: Molecular analysis in true hermaphroditism: demonstration of low-level hidden mosaicism for Y-derived sequences in 46,XX cases.
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ABSTRACT: True hermaphroditism (TH) is an unusual form of sex reversal, characterized by the development of testicular and ovarian tissue in the same subject. Approximately 60% of the patients have a 46,XX karyotype, 33% are mosaics with a second cell line containing a Y chromosome, while the remaining 7% are 46,XY. Molecular analyses have demonstrated that SRY is present in only 10% of TH with a 46,XX karyotype; therefore, in the remaining 90%, mutations at unknown X-linked or autosomal sex determining loci have been proposed as factors responsible for testicular development. True hermaphroditism presents considerable genetic heterogeneity with several molecular anomalies leading to the dual gonadal development as SRY point mutations or SRY hidden gonadal mosaicism. In order to identify genetic defects associated with subjects with the disease, we performed molecular analyses of the SRY gene in DNA from blood leukocytes and gonadal tissue in 12 true hermaphrodites with different karyotypes. Our results using PCR and FISH analyses reveal the presence of hidden mosaicism for SRY or other Y sequences in some patients with XX true hermaphroditism and confirms that mosaicism for SRY limited to the gonads is an alternative mechanism for testicular development in 46,XX true hermaphrodites.Human Genetics 10/2002; 111(3):278-83. · 5.07 Impact Factor -
Article: Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site.
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ABSTRACT: GnRH regulates the synthesis and release of pituitary gonadotropins. Mutations in the human GnRH receptor (hGnRHR) gene have been reported in families with hypogonadotropic hypogonadism. Our group recently described a novel homozygous E(90)K mutation of the hGnRHR in two siblings with the complete form of hypogonadotropic hypogonadism. In the present study, mutational analysis of the E(90)K substitution was performed to assess the functional role of this particular residue, which is located in the second transmembrane helix of the hGnRHR. Although E(90) is highly conserved in all other known mammalian GnRH receptors, this residue has not been previously implicated in GnRH binding and/or GnRHR activation. Transient expression of the mutant E(90)K receptor in COS-7 cells resulted in a virtual abolition of GnRH agonist binding and agonist-stimulated phosphoinositide turnover, initially suggesting that E(90) may be essential for GnRH binding. Furthermore, incubation with 1 microM of different GnRH agonists (D-Trp(6)-GnRH, GnRH, leuprolide, Catfish-1 GnRH, Catfish-2 GnRH, D-Lys(6)-Pro(9)-EA-GnRH, DesGly(10)-GnRH, D-Trp(6)-Pro(9)-EA-GnRH, Buserelin, and D-Lys(6)-GnRH) or antagonists (Antide and "Nal-Arg") did not result in elevated inositol phosphate production from cells expressing the E(90)K mutant. To examine the role of a site known to suppress hGnRHR function, mutants with deletion of K(191) (DeltaK(191)) from the hGnRHR and/or addition of catfish GnRHR intracellular carboxyl-terminal tail (cfCtail) to hGnRHR were prepared. Exposure to the GnRH analog Buserelin resulted in a significant increase in total inositol phosphate production in cells expressing the hGnRHR-cfCtail, hGnRHR(DeltaK(191)) and hGnRHR(DeltaK(191))-cfCtail. Activation of intracellular signaling in response to Buserelin was restored by deletion of K(191) from the E(90)K mutant receptor but minimally by addition of the catfish GnRHR carboxyl-terminal tail. There were no significant differences in total inositol phosphate production between the chimeric receptors bearing the DeltaK(191) or the E(90)K/DeltaK(191) modifications. All but the (E(90)K) and (E(90)K)-cfCtail altered receptors were membrane expressed as disclosed by Western blot analysis of epitope-tagged receptors. This study provides evidence that the E(90)K mutation impairs hGnRHR-effector coupling. The observation that sequence modifications that enhance surface expression of the receptor restore function, presents the possibility that loss of surface expression may underlie the severe phenotype exhibited by hypogonadotropic hypogonadism patients bearing this mutational defect.Journal of Clinical Endocrinology & Metabolism 06/2002; 87(5):2144-9. · 6.50 Impact Factor -
Article: Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors.
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ABSTRACT: Inactivating mutations of the luteinizing hormone receptor (LHR) gene in males induce Leydig cell agenesis or hypoplasia, while activating mutations cause testotoxicosis. Recently, it was demonstrated that a somatic heterozygous activating mutation of the LHR gene (Asp578His), limited to the tumor, was the cause of Leydig cell adenomas in three unrelated patients. We describe the molecular study of two unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas. Genomic DNA was extracted from the tumor, the adjacent normal testis tissue, and blood leukocytes. Both individuals exhibited an heterozygous missense mutation, limited only to the tumor, consisting of a guanine (G) to cytosine (C) substitution at codon 578 (GAT to CAT), turning aspartic acid into histidine. The presence of the same mutation in different ethnic groups demonstrates the existence of a mutational hot spot in the LHR gene. Indeed, this mutation occurs at the conserved aspartic acid residue at amino acid 578, where a substitution by glycine is the most common mutation observed in testotoxicosis and where a substitution by tyrosine has been linked to a more severe clinical phenotype where diffuse Leydig cell hyperplasia is found. Our results confirm the fact that somatic activating mutations of gonadotropin receptors are involved in gonadal tumorigenesis.American Journal of Medical Genetics 04/2002; 108(2):148-52.
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Institutions
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2002–2006
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Mexican Institute of Social Security
Mexico City, The Federal District, Mexico
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