The Experts below are selected from a list of 156 Experts worldwide ranked by ideXlab platform
Martine Caron - One of the best experts on this subject based on the ideXlab platform.
-
molecular analysis of the insulin receptor gene for prenatal diagnosis of Leprechaunism in two families
Prenatal Diagnosis, 1997Co-Authors: Christele Desboismouthon, Emmanuelle Girodon, N Ghanem, Martine Caron, A Pennerath, Patricia Conteville, Jocelyne Magre, Claude Besmond, Marcel Goossens, Jacqueline CapeauAbstract:: Leprechaunism is a rare autosomal recessive disorder characterized by marked intrauterine and postnatal growth retardation, severe insulin resistance, and altered glucose homeostasis. This syndrome is related to mutations in the insulin receptor (IR) gene that impair the transmission of the insulin signal by several mechanisms. There is no effective therapy and patients usually die within the first months of life. Here we report the prenatal diagnosis of Leprechaunism in two unrelated families in which affected children were compound heterozygotes with two different deficient IR alleles. In family Par-1, the disease IR alleles carried a missense mutation located in exon 18 (Arg1092-->Trp) and exon 20 (Glu1179-->Lys). In family Als, a 3-basepair deletion causing the loss of Asn281 in exon 3 and a major deletion of exons 10-13 were present in the maternal and paternal mutant IR alleles, respectively. Prenatal diagnosis was made in each family by a specific approach combining denaturing gradient gel electrophoresis (DGGE) and Southern blotting. This methodology allowed us to correctly predict the genotype of the two fetuses at the IR locus.
-
severe resistance to insulin and insulin like growth factor i in cells from a patient with Leprechaunism as a result of two mutations in the tyrosine kinase domain of the insulin receptor
Metabolism-clinical and Experimental, 1996Co-Authors: Christele Desboismouthon, Claude Besmond, Jacqueline Capeau, Claude Danan, Serge Amselem, Mariejose Blivetvan Eggelpoel, Caroline Sertlangeron, Michel Goossens, Martine CaronAbstract:Abstract We studied the biological properties of insulin receptors (IRs) and insulin-like growth factor-I (IGF-I) receptors in cultured fibroblasts from a patient with Leprechaunism (leprechaun Par-1). Patient cells displayed normal insulin binding capacity and affinity. Basal in vivo auto phosphorylation and in vitro exogenous kinase activity of patient IRs were elevated twofold to threefold compared with control receptors, and insulin had no further effect on these processes. Moreover, patient IRs were unable to promote the stimulation of metabolic and mitogenic pathways. IR substrate-1 (IRS-1) and mitogen-activated protein (MAP) kinase tyrosine phosphorylation and glycogen and DNA synthesis were not increased in the basal state in patient fibroblasts and were also insensitive to the stimulatory effect of insulin. As for IGF-I, although binding and receptor kinase activity were normal, the ability to stimulate glycogen and DNA synthesis was altered in patient cells. Two mutant alleles of the IR gene were detected by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The maternal allele contained a point mutation in exon 18 encoding the tryptophan-for-arginine substitution at position 1092, and the paternal allele had a point mutation in exon 20 substituting lysine for glutamic acid at codon 1179. Thereby, leprechaun Par-1 was a compound heterozygote for two missense mutations located in the IR β-subunit. The present investigation provides the first evidence that Leprechaunism can be causally related to structural alterations in the tyrosine kinase domain of the IR. These alterations result in severe impairment of insulin and IGF-I action.
Toshihiro Tajima - One of the best experts on this subject based on the ideXlab platform.
-
development of endometrial carcinoma in a patient with Leprechaunism donohue syndrome
Clinical Pediatric Endocrinology, 2013Co-Authors: Wakako Jo, Satoko Sudo, Akie Nakamura, Daisuke Endo, Yosuke Konno, Katsura Ishizu, Toshihiro TajimaAbstract:Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of Leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with Leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease.
-
Leprechaunism caused by mutations in the insulin receptor gene
Nihon rinsho. Japanese journal of clinical medicine, 2002Co-Authors: Mari Murashita, Toshihiro Tajima, Jun Nakae, Kenji FujiedaAbstract:: Leprechaunism represents the most severe form of insulin resistance syndrome, manifesting abnormal glucose metabolism and intrauterine, postnatal growth retardation. Mutations in both alleles of the insulin receptor gene have been identified. Recombinant human IGF-I treatment could prevent postnatal growth retardation and normalize glucose metabolism, however there are few reports of long-term treatment with IGF-I. We have a case of compound heterozygous mutations of the insulin receptor gene, who has been treated with IGF-I more than 11 years. Relatively higher dose of IGF-I is necessary for maintaining sufficient serum IGF-I levels. After 10 years' treatment with IGF-I, polycystic ovary, kidney enlargement, albuminuria and retinopathy are complicated in this patient. In this review, we summarized basic actions of insulin and insulin receptor, classification of mutations in the insulin receptor gene, clinical feature and our results of long-term treatment with IGF-I in Leprechaunism.
-
long term effect of recombinant human insulin like growth factor i on metabolic and growth control in a patient with Leprechaunism
The Journal of Clinical Endocrinology and Metabolism, 1998Co-Authors: Jun Nakae, Toshihiro Tajima, Mari Murashita, Mikiko Kato, Nozomi Shinohara, Kenji FujiedaAbstract:Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with Leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient’s fibroblasts showed normal binding of IGF-I, normal phosphorylation of the β-subunit of the IGF-I receptor, and normal[ 3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increa...
Richard W Furlanetto - One of the best experts on this subject based on the ideXlab platform.
-
homozygous nonsense mutation in the insulin receptor gene of a patient with severe congenital insulin resistance Leprechaunism and the role of the insulin like growth factor receptor
Clinical Endocrinology, 1996Co-Authors: Nicholas Kaplowitz, Richard W FurlanettoAbstract:Severe congenital insulin resistance in the syndrome of Leprechaunism is caused by mutations in the insulin receptor gene. We report a patient with Leprechaunism who was homozygous for a mutation resulting in the absence of cell surface insulin receptors. To determine whether the receptor for Insulin-like growth factor-I (IGF-I) is involved in the phenotype of Leprechaunism, we studied the effect of insulin and of IGF-I on cells from this patient. The patient had a homozygous C → T substitution at base pair 8212 in exon 12 of the insulin receptor gene, creating a premature stop codon. This nonsense mutation is in the extracellular portion of the receptor and truncates the insulin receptor proximal to its transmembrane anchor, resulting in the absence of cell surface insulin receptors. This finding indicates that complete absence of the insulin receptor is compatible with life. Secondly, DNA synthesis was studied in skin derived fibroblasts in response to increasing concentrations of either insulin or Insulin-like growth factor -I (IGF-I), and was assessed by 3H-thymidine incorporation. In this patient’s cells, both of these hormones increased 3H-thymidine incorporation, and the effect was blocked by α-IR3, a monoclonal antibody that blocks activation of the IGF-I receptor. These findings confirmed the absence of the insulin receptor and indicated that insulin acts here through activation of the IGF-I receptor. These data support the contention that the phenotypic and metabolic abnormalities of Leprechaunism result from the combination of lack of insulin receptor action and over-activation by insulin of the type 1 IGF receptor.
-
deletion of 3 basepairs resulting in the loss of lysine 121 in the insulin receptor alpha subunit in a patient with Leprechaunism binding phosphorylation and biological activity
The Journal of Clinical Endocrinology and Metabolism, 1994Co-Authors: Nicholas Jospe, James N Livingston, Richard W FurlanettoAbstract:We have identified a novel mutation of the human insulin receptor gene in a previously unreported patient with Leprechaunism, leprechaun Rochester. This mutation consists of deletion of three nucleotides (GAA) in exon 2 and results in loss of the lysine-121 in the putative ligand-binding domain of the alpha-subunit. To analyze this mutation, we prepared a corresponding mutant insulin receptor by site-directed mutagenesis and expressed the receptor in Chinese hamster ovary cells. Although the mutant receptor displayed normal insulin binding, abnormalities were found in autophosphorylation and in phosphorylation of endogenous and exogenous protein substrates. These abnormalities consisted of increased basal kinase activity, but blunted insulin-stimulated responsiveness. Importantly, cells that expressed the mutant receptor showed markedly decreased insulin- and serum-stimulated DNA synthesis compared to untransfected control cells and cells transfected with the wild-type insulin receptor. These findings sug...
Purificacion Rodriguezcernuda - One of the best experts on this subject based on the ideXlab platform.
-
areolar sebaceous hyperplasia with underlying primary duct carcinoma of the breast in a woman with donohue syndrome Leprechaunism
American Journal of Dermatopathology, 2012Co-Authors: Angel Fernandezflores, Saul Valerdiz, Luis G Crespo, Purificacion RodriguezcernudaAbstract:AbstractAreolar hyperplasia is only reported when exaggerated, and even so, exaggerated areolar sebaceous hyperplasia is rare. We have recently seen a case of areolar sebaceous hyperplasia in a 32-year-old woman with Donohue syndrome (Leprechaunism), who also had an invasive ductal carcinoma in the
-
areolar sebaceous hyperplasia with underlying primary duct carcinoma of the breast in a woman with donohue syndrome Leprechaunism
American Journal of Dermatopathology, 2012Co-Authors: Angel Fernandezflores, Saul Valerdiz, Luis G Crespo, Purificacion RodriguezcernudaAbstract:: Areolar hyperplasia is only reported when exaggerated, and even so, exaggerated areolar sebaceous hyperplasia is rare. We have recently seen a case of areolar sebaceous hyperplasia in a 32-year-old woman with Donohue syndrome (Leprechaunism), who also had an invasive ductal carcinoma in the same breast. The patient showed typical "elfin-like" face with wide nostrils and thick lips, large and low-set ears, and dysplastic nails. The areola showed a yellowish thickened plaque of 5-cm diameter that corresponded to a hyperplasia of the sebaceous glands. Immunohistochemistry for the mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) was performed on the sebaceous hyperplasia and on the breast carcinoma, and no lack of expression of the markers was evidenced. We have found no other reported case of areolar sebaceous hyperplasia either in cases of breast carcinoma or in cases of Leprechaunism.
Christele Desboismouthon - One of the best experts on this subject based on the ideXlab platform.
-
molecular analysis of the insulin receptor gene for prenatal diagnosis of Leprechaunism in two families
Prenatal Diagnosis, 1997Co-Authors: Christele Desboismouthon, Emmanuelle Girodon, N Ghanem, Martine Caron, A Pennerath, Patricia Conteville, Jocelyne Magre, Claude Besmond, Marcel Goossens, Jacqueline CapeauAbstract:: Leprechaunism is a rare autosomal recessive disorder characterized by marked intrauterine and postnatal growth retardation, severe insulin resistance, and altered glucose homeostasis. This syndrome is related to mutations in the insulin receptor (IR) gene that impair the transmission of the insulin signal by several mechanisms. There is no effective therapy and patients usually die within the first months of life. Here we report the prenatal diagnosis of Leprechaunism in two unrelated families in which affected children were compound heterozygotes with two different deficient IR alleles. In family Par-1, the disease IR alleles carried a missense mutation located in exon 18 (Arg1092-->Trp) and exon 20 (Glu1179-->Lys). In family Als, a 3-basepair deletion causing the loss of Asn281 in exon 3 and a major deletion of exons 10-13 were present in the maternal and paternal mutant IR alleles, respectively. Prenatal diagnosis was made in each family by a specific approach combining denaturing gradient gel electrophoresis (DGGE) and Southern blotting. This methodology allowed us to correctly predict the genotype of the two fetuses at the IR locus.
-
severe resistance to insulin and insulin like growth factor i in cells from a patient with Leprechaunism as a result of two mutations in the tyrosine kinase domain of the insulin receptor
Metabolism-clinical and Experimental, 1996Co-Authors: Christele Desboismouthon, Claude Besmond, Jacqueline Capeau, Claude Danan, Serge Amselem, Mariejose Blivetvan Eggelpoel, Caroline Sertlangeron, Michel Goossens, Martine CaronAbstract:Abstract We studied the biological properties of insulin receptors (IRs) and insulin-like growth factor-I (IGF-I) receptors in cultured fibroblasts from a patient with Leprechaunism (leprechaun Par-1). Patient cells displayed normal insulin binding capacity and affinity. Basal in vivo auto phosphorylation and in vitro exogenous kinase activity of patient IRs were elevated twofold to threefold compared with control receptors, and insulin had no further effect on these processes. Moreover, patient IRs were unable to promote the stimulation of metabolic and mitogenic pathways. IR substrate-1 (IRS-1) and mitogen-activated protein (MAP) kinase tyrosine phosphorylation and glycogen and DNA synthesis were not increased in the basal state in patient fibroblasts and were also insensitive to the stimulatory effect of insulin. As for IGF-I, although binding and receptor kinase activity were normal, the ability to stimulate glycogen and DNA synthesis was altered in patient cells. Two mutant alleles of the IR gene were detected by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The maternal allele contained a point mutation in exon 18 encoding the tryptophan-for-arginine substitution at position 1092, and the paternal allele had a point mutation in exon 20 substituting lysine for glutamic acid at codon 1179. Thereby, leprechaun Par-1 was a compound heterozygote for two missense mutations located in the IR β-subunit. The present investigation provides the first evidence that Leprechaunism can be causally related to structural alterations in the tyrosine kinase domain of the IR. These alterations result in severe impairment of insulin and IGF-I action.