The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform

Axel P N Themmen - One of the best experts on this subject based on the ideXlab platform.

  • Mutant Luteinizing Hormone Receptors in a Compound Heterozygous Patient with Complete Leydig Cell Hypoplasia: Abnormal Processing Causes Signaling Deficiency
    2014
    Co-Authors: John W M Martens, Serge Lumbroso, Virginie Georget, T E Romer, Axel P N Themmen, H G Brunner, M. Verhoef-post, A. Richter-unruh, M. Szarras-czapnik, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the pater-nal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely de-void of hormone-induced cAMP reporter gene activation. Us-ing Western blotting of expressed LH receptor protein with

  • mutations in a novel cryptic exon of the luteinizing hormone chorionic gonadotropin receptor gene cause male pseudohermaphroditism
    PLOS Medicine, 2008
    Co-Authors: Nina Kossack, Annette Richterunruh, Axel P N Themmen, Manuela Simoni, Jorg Gromoll
    Abstract:

    Background Male pseudohermaphroditism, or Leydig Cell Hypoplasia (LCH), is an autosomal recessive disorder in individuals with a 46,XY karyotype, characterized by a predominantly female phenotype, a blind-ending vagina, absence of breast development, primary amenorrhea, and the presence of testicular structures. It is caused by mutations in the luteinizing hormone/ chorionic gonadotropin receptor gene (LHCGR), which impair either LH/CG binding or signal transduction. However, molecular analysis has revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH. We therefore searched the LHCGR for novel genomic elements causative for LCH.

  • Mutations in a novel, cryptic exon of the luteinizing hormone/chorionic gonadotropin receptor gene cause male pseudohermaphroditism.
    Public Library of Science (PLoS), 2008
    Co-Authors: Nina Kossack, Axel P N Themmen, Manuela Simoni, Annette Richter-unruh, Jorg Gromoll
    Abstract:

    Male pseudohermaphroditism, or Leydig Cell Hypoplasia (LCH), is an autosomal recessive disorder in individuals with a 46,XY karyotype, characterized by a predominantly female phenotype, a blind-ending vagina, absence of breast development, primary amenorrhea, and the presence of testicular structures. It is caused by mutations in the luteinizing hormone/chorionic gonadotropin receptor gene (LHCGR), which impair either LH/CG binding or signal transduction. However, molecular analysis has revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH. We therefore searched the LHCGR for novel genomic elements causative for LCH.In the present study we have identified a novel, primate-specific bona fide exon (exon 6A) within the LHCGR gene. It displays composite characteristics of an internal/terminal exon and possesses stop codons triggering nonsense-mediated mRNA decay (NMD) in LHCGR. Transcripts including exon 6A are physiologically highly expressed in human testes and granulosa Cells, and result in an intraCellular, truncated LHCGR protein of 209 amino acids. We sequenced exon 6A in 16 patients with unexplained LCH and detected mutations in three patients. Functional studies revealed a dramatic increase in the expression of the mutated internal exon 6A transcripts, indicating aberrant NMD. These altered ratios of LHCGR transcripts result in the generation of predominantly nonfunctional LHCGR isoforms, thereby preventing proper expression and functioning.The identification and characterization of this novel exon not only identifies a new regulatory element within the genomic organization of LHCGR, but also points toward a complex network of receptor regulation, including events at the transcriptional level. These findings add to the molecular diagnostic tools for LCH and extend our understanding of the endocrine regulation of sexual differentiation

  • mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig Cell Hypoplasia abnormal processing causes signaling deficiency
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: John W M Martens, Serge Lumbroso, Miriam Verhoefpost, Virginie Georget, Annette Richterunruh, Maria Szarrasczapnik, T E Romer, Han G Brunner, Axel P N Themmen, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and Cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the Cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the Cell surface and results in complete Leydig Cell Hypoplasia in this patient.

  • a homozygous mutation in the luteinizing hormone receptor causes partial Leydig Cell Hypoplasia correlation between receptor activity and phenotype
    Molecular Endocrinology, 1998
    Co-Authors: John W M Martens, Miriam Verhoefpost, Han G Brunner, Sergio P A Toledo, N M A Abelin, M C L Ezabella, Axel P N Themmen
    Abstract:

    Leydig Cell Hypoplasia (LCH) is characterized by a decreased response of the Leydig Cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 Cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low Cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low Cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor Cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of Cell surface expression and coupling efficiency.

John W M Martens - One of the best experts on this subject based on the ideXlab platform.

  • Mutant Luteinizing Hormone Receptors in a Compound Heterozygous Patient with Complete Leydig Cell Hypoplasia: Abnormal Processing Causes Signaling Deficiency
    2014
    Co-Authors: John W M Martens, Serge Lumbroso, Virginie Georget, T E Romer, Axel P N Themmen, H G Brunner, M. Verhoef-post, A. Richter-unruh, M. Szarras-czapnik, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the pater-nal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely de-void of hormone-induced cAMP reporter gene activation. Us-ing Western blotting of expressed LH receptor protein with

  • mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig Cell Hypoplasia abnormal processing causes signaling deficiency
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: John W M Martens, Serge Lumbroso, Miriam Verhoefpost, Virginie Georget, Annette Richterunruh, Maria Szarrasczapnik, T E Romer, Han G Brunner, Axel P N Themmen, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and Cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the Cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the Cell surface and results in complete Leydig Cell Hypoplasia in this patient.

  • Leydig Cell Hypoplasia cases with new mutations new polymorphisms and cases without mutations in the luteinizing hormone receptor gene
    Clinical Endocrinology, 2002
    Co-Authors: Annette Richterunruh, John W M Martens, Miriam Verhoefpost, Sergio P A Toledo, H T Wessels, W A Kors, G H G Sinnecker, Annemie L M Boehmer, S L S Drop, H G Brunner
    Abstract:

    Summary background Defective male sex differentiation in patients with Hypoplasia of Leydig Cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. patients and methods Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron–exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45–59 healthy persons using denaturation high-performance liquid chromatography. results Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1·7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. conclusions Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.

  • a homozygous mutation in the luteinizing hormone receptor causes partial Leydig Cell Hypoplasia correlation between receptor activity and phenotype
    Molecular Endocrinology, 1998
    Co-Authors: John W M Martens, Miriam Verhoefpost, Han G Brunner, Sergio P A Toledo, N M A Abelin, M C L Ezabella, Axel P N Themmen
    Abstract:

    Leydig Cell Hypoplasia (LCH) is characterized by a decreased response of the Leydig Cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 Cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low Cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low Cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor Cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of Cell surface expression and coupling efficiency.

  • Themmen: A homozygous mutation in the luteinizing hormone receptor causes partial Leydig Cell Hypoplasia: correlation between receptor activity and phenotype
    1998
    Co-Authors: John W M Martens, Han G Brunner, Axel P N Themmen, Sergio P A Toledo, N M A Abelin, M C L Ezabella, Miriam Verhoef-post, Endocrine Division
    Abstract:

    Leydig Cell Hypoplasia (LCH) is characterized by a decreased response of the Leydig Cells to LH. As a result, patients with this syndrome display aber-rant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene re-vealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 Cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low Cell sur-face expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low Cell surface expression and decreased coupling effi-ciency. For LHR(A593P), the absence of a reduced response resulted from both poor Cell surface ex-pression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of Cell surface expression and coupling efficiency. (Molecular Endocrinology 12: 775–784, 1998

Sergio P A Toledo - One of the best experts on this subject based on the ideXlab platform.

  • Leydig Cell Hypoplasia cases with new mutations new polymorphisms and cases without mutations in the luteinizing hormone receptor gene
    Clinical Endocrinology, 2002
    Co-Authors: Annette Richterunruh, John W M Martens, Miriam Verhoefpost, Sergio P A Toledo, H T Wessels, W A Kors, G H G Sinnecker, Annemie L M Boehmer, S L S Drop, H G Brunner
    Abstract:

    Summary background Defective male sex differentiation in patients with Hypoplasia of Leydig Cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. patients and methods Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron–exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45–59 healthy persons using denaturation high-performance liquid chromatography. results Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1·7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. conclusions Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.

  • a homozygous mutation in the luteinizing hormone receptor causes partial Leydig Cell Hypoplasia correlation between receptor activity and phenotype
    Molecular Endocrinology, 1998
    Co-Authors: John W M Martens, Miriam Verhoefpost, Han G Brunner, Sergio P A Toledo, N M A Abelin, M C L Ezabella, Axel P N Themmen
    Abstract:

    Leydig Cell Hypoplasia (LCH) is characterized by a decreased response of the Leydig Cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 Cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low Cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low Cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor Cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of Cell surface expression and coupling efficiency.

  • Themmen: A homozygous mutation in the luteinizing hormone receptor causes partial Leydig Cell Hypoplasia: correlation between receptor activity and phenotype
    1998
    Co-Authors: John W M Martens, Han G Brunner, Axel P N Themmen, Sergio P A Toledo, N M A Abelin, M C L Ezabella, Miriam Verhoef-post, Endocrine Division
    Abstract:

    Leydig Cell Hypoplasia (LCH) is characterized by a decreased response of the Leydig Cells to LH. As a result, patients with this syndrome display aber-rant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene re-vealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 Cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low Cell sur-face expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low Cell surface expression and decreased coupling effi-ciency. For LHR(A593P), the absence of a reduced response resulted from both poor Cell surface ex-pression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of Cell surface expression and coupling efficiency. (Molecular Endocrinology 12: 775–784, 1998

  • an inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46 xx female
    The Journal of Clinical Endocrinology and Metabolism, 1996
    Co-Authors: Sergio P A Toledo, Robert Kraaij, M Post, H G Brunner, Patricia L M Dahia, C Y Hayashida, A Kremer P H Themmen
    Abstract:

    Hypergonadotropic hypogonadism is characterized by decreased gonadal function due to the inability of the gonads to respond to pituitary gonadotropins. Hypergonadotropic hypogonadism in females has many causes, among which are ovarian dysgenesis and abnormalities of the ovarian receptors for the pituitary gonadotropins. We evaluated a woman who presented with amenorrhea due to hypergonadotropic hypogonadism, but who had structurally normal ovaries. She is a sister of two previously identified 46,XY male pseudohermaphrodites with Leydig Cell Hypoplasia. Injection of hCG did not cause any change in plasma levels of estradiol or progesterone, suggesting complete ovarian resistance to LH. Analysis of the DNA sequence of the LH receptor gene revealed that the patient is homozygous for the same single base change as her two brothers. This mutation causes substitution of an alanine residue by a proline at position 593. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 Cells documented that the receptor is unable to stimulate adenylyl cyclase in response to hCG. Plasma levels of estradiol and progesterone were low, whereas LH and FSH levels were increased. On histological analysis of the ovary, follicles were seen at all developmental stages. Nonetheless, primary amenorrhea had been present for 5 yr, and repeated measurements of plasma estradiol and progesterone indicate that ovulation does not occur. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women. The combined clinical and molecular observations are consistent with previous experimental data suggesting that in humans, LH is necessary for ovulation but follicular maturation can occur in the presence of FSH alone.

  • male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene
    Nature Genetics, 1995
    Co-Authors: J M J Kremer, E Milgrom, Robert Kraaij, Sergio P A Toledo, M Post, J B Fridman, Cesar Y Hayashida, M Van Reen, H H Ropers, Edwin M Mariman
    Abstract:

    Leydig Cell Hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied two Leydig Cell Hypoplasia patients (siblings born to consanguineous parents), and found them to be homozygous for a missense mutation (Ala593Pro) in the sixth transmembrane domain of the luteinizing hormone (LH) receptor gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin with a normal KD, but the ligand binding does not result in increased production of cAMP. We conclude that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig Cell Hypoplasia in this family. These results have implications for the understanding of the development of the male genitalia.

Annette Richterunruh - One of the best experts on this subject based on the ideXlab platform.

  • mutations in a novel cryptic exon of the luteinizing hormone chorionic gonadotropin receptor gene cause male pseudohermaphroditism
    PLOS Medicine, 2008
    Co-Authors: Nina Kossack, Annette Richterunruh, Axel P N Themmen, Manuela Simoni, Jorg Gromoll
    Abstract:

    Background Male pseudohermaphroditism, or Leydig Cell Hypoplasia (LCH), is an autosomal recessive disorder in individuals with a 46,XY karyotype, characterized by a predominantly female phenotype, a blind-ending vagina, absence of breast development, primary amenorrhea, and the presence of testicular structures. It is caused by mutations in the luteinizing hormone/ chorionic gonadotropin receptor gene (LHCGR), which impair either LH/CG binding or signal transduction. However, molecular analysis has revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH. We therefore searched the LHCGR for novel genomic elements causative for LCH.

  • mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig Cell Hypoplasia abnormal processing causes signaling deficiency
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: John W M Martens, Serge Lumbroso, Miriam Verhoefpost, Virginie Georget, Annette Richterunruh, Maria Szarrasczapnik, T E Romer, Han G Brunner, Axel P N Themmen, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and Cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the Cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the Cell surface and results in complete Leydig Cell Hypoplasia in this patient.

  • Leydig Cell Hypoplasia cases with new mutations new polymorphisms and cases without mutations in the luteinizing hormone receptor gene
    Clinical Endocrinology, 2002
    Co-Authors: Annette Richterunruh, John W M Martens, Miriam Verhoefpost, Sergio P A Toledo, H T Wessels, W A Kors, G H G Sinnecker, Annemie L M Boehmer, S L S Drop, H G Brunner
    Abstract:

    Summary background Defective male sex differentiation in patients with Hypoplasia of Leydig Cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. patients and methods Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1–10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron–exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45–59 healthy persons using denaturation high-performance liquid chromatography. results Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1·7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. conclusions Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed.

C Sultan - One of the best experts on this subject based on the ideXlab platform.

  • Mutant Luteinizing Hormone Receptors in a Compound Heterozygous Patient with Complete Leydig Cell Hypoplasia: Abnormal Processing Causes Signaling Deficiency
    2014
    Co-Authors: John W M Martens, Serge Lumbroso, Virginie Georget, T E Romer, Axel P N Themmen, H G Brunner, M. Verhoef-post, A. Richter-unruh, M. Szarras-czapnik, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the pater-nal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely de-void of hormone-induced cAMP reporter gene activation. Us-ing Western blotting of expressed LH receptor protein with

  • mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig Cell Hypoplasia abnormal processing causes signaling deficiency
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: John W M Martens, Serge Lumbroso, Miriam Verhoefpost, Virginie Georget, Annette Richterunruh, Maria Szarrasczapnik, T E Romer, Han G Brunner, Axel P N Themmen, C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and Cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the Cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the Cell surface and results in complete Leydig Cell Hypoplasia in this patient.

  • Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig Cell Hypoplasia: abnormal processing causes signaling deficiency
    2002
    Co-Authors: Martens J.w.m., Lumbroso S., Verhoef-post M., Richter-unruh A., Szarras-czapnik M., Romer T.e., Brunner H.g., Themmen A.p.n., C Sultan
    Abstract:

    Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig Cell Hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig Hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and Cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected