The Experts below are selected from a list of 4314 Experts worldwide ranked by ideXlab platform
Peter Wieacker - One of the best experts on this subject based on the ideXlab platform.
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frame shift mutation of LHX1 is associated with mayer rokitansky kuster hauser mrkh syndrome
Human Reproduction, 2012Co-Authors: S Ledig, Sara Y Brucker, Gianmaria Barresi, J Schomburg, K Rall, Peter WieackerAbstract:BACKGROUND The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women who usually have normal ovaries and a 46, XX karyotype. MRKH can occur as an isolated form (type I) or in combination with various malformations as a syndromic or a type II MRKH. To date, in most of the cases the underlying etiology remains unclear. Recently, in approximately 6% of MRKH patients, deletions of chromosomal region 17q12 have been identified. The LHX1 gene, which is located in the deletion interval, has been suggested to be a strong candidate, because targeting inactivation of LHX1 causes a complex phenotype including aplasia of the Mullerian ducts. METHODS AND RESULTS By sequence analysis of LHX1 in a large cohort of MRKH patients, we detected a heterozygous frame shift mutation resulting in a premature stop codon. Previously, we have reported a heterozygous missense mutation of LHX1 in another MRKH patient. CONCLUSIONS We conclude that heterozygous mutations of LHX1 might be one cause of the MRKH syndrome in a subgroup of patients.
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recurrent aberrations identified by array cgh in patients with mayer rokitansky kuster hauser syndrome
Fertility and Sterility, 2011Co-Authors: S Ledig, Cordula Schippert, Reiner Strick, Matthias W Beckmann, P Oppelt, Peter WieackerAbstract:Objective To identify genetic causes of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Design Prospective laboratory study. Setting University hospital. Patient(s) Fifty-six patients with MRKH syndrome. Intervention(s) Identification of microdeletions and –duplications in a group of 48 MRKH patients by array-CGH. Results obtained by array-CGH were confirmed by RT-qPCR. Sequential analysis of two candidate genes LHX1 and HNF1B in a group of 56 MRKH patients. Main Outcome Measure(s) Identification of chromosomal regions and genes (recurrent and private) associated with MRKH syndrome. Result(s) We could delineate three definitively relevant regions (1q21.1, 17q12, and 22q11.21) and suggest that LHX1 und HNF1B are candidate genes for MRKH syndrome, because we identified recurrent deletions affecting these genes and a possible causative missense mutation in LHX1 . Conclusion(s) Our findings suggest that different chromosomal regions are associated with MRKH syndrome.
Daniel I Chasman - One of the best experts on this subject based on the ideXlab platform.
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multi ancestry study of blood lipid levels identifies four loci interacting with physical activity
Nature Communications, 2019Co-Authors: Tuomas O Kilpelainen, Amy R Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W Winkler, Hermina Jakupovic, Daniel I ChasmanAbstract:Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
S Ledig - One of the best experts on this subject based on the ideXlab platform.
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frame shift mutation of LHX1 is associated with mayer rokitansky kuster hauser mrkh syndrome
Human Reproduction, 2012Co-Authors: S Ledig, Sara Y Brucker, Gianmaria Barresi, J Schomburg, K Rall, Peter WieackerAbstract:BACKGROUND The Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women who usually have normal ovaries and a 46, XX karyotype. MRKH can occur as an isolated form (type I) or in combination with various malformations as a syndromic or a type II MRKH. To date, in most of the cases the underlying etiology remains unclear. Recently, in approximately 6% of MRKH patients, deletions of chromosomal region 17q12 have been identified. The LHX1 gene, which is located in the deletion interval, has been suggested to be a strong candidate, because targeting inactivation of LHX1 causes a complex phenotype including aplasia of the Mullerian ducts. METHODS AND RESULTS By sequence analysis of LHX1 in a large cohort of MRKH patients, we detected a heterozygous frame shift mutation resulting in a premature stop codon. Previously, we have reported a heterozygous missense mutation of LHX1 in another MRKH patient. CONCLUSIONS We conclude that heterozygous mutations of LHX1 might be one cause of the MRKH syndrome in a subgroup of patients.
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recurrent aberrations identified by array cgh in patients with mayer rokitansky kuster hauser syndrome
Fertility and Sterility, 2011Co-Authors: S Ledig, Cordula Schippert, Reiner Strick, Matthias W Beckmann, P Oppelt, Peter WieackerAbstract:Objective To identify genetic causes of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Design Prospective laboratory study. Setting University hospital. Patient(s) Fifty-six patients with MRKH syndrome. Intervention(s) Identification of microdeletions and –duplications in a group of 48 MRKH patients by array-CGH. Results obtained by array-CGH were confirmed by RT-qPCR. Sequential analysis of two candidate genes LHX1 and HNF1B in a group of 56 MRKH patients. Main Outcome Measure(s) Identification of chromosomal regions and genes (recurrent and private) associated with MRKH syndrome. Result(s) We could delineate three definitively relevant regions (1q21.1, 17q12, and 22q11.21) and suggest that LHX1 und HNF1B are candidate genes for MRKH syndrome, because we identified recurrent deletions affecting these genes and a possible causative missense mutation in LHX1 . Conclusion(s) Our findings suggest that different chromosomal regions are associated with MRKH syndrome.
Simon J. Rhodes - One of the best experts on this subject based on the ideXlab platform.
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The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter.
Molecular endocrinology (Baltimore Md.), 2006Co-Authors: Anne Granger, Simon J. Rhodes, Christian Bleux, Marie Laure Kottler, Raymond Counis, Jean Noël LaverrièreAbstract:The GnRH receptor (GnRH-R) plays a central role in mammalian reproductive function throughout adulthood. It also appears as an early marker gene of the presumptive gonadotrope lineage in developing pituitary. Here, using transient transfections combined with DNA/protein interaction assays, we have delineated cis-acting elements within the rat GnRH-R gene promoter that represent targets for the LIM-homeodomain (LIM-HD) proteins, Isl-1 and Lhx3. These factors, critical in early pituitary development, are thus also crucial for gonadotrope-specific expression of the GnRH-R gene. In heterologous cells, the expression of Isl-1 and Lhx3, together with steroidogenic factor 1 (SF-1), culminates in the activation of both the rat as well as human GnRH-R promoter, suggesting that this combination is evolutionarily conserved among mammals. The specificity of these LIM-HD factors is attested by the inefficiency of related proteins, including Lhx5 and Lhx9, to activate the GnRH-R gene promoter, as well as by the repress...
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Regulation of the Follicle-Stimulating Hormone β Gene by the LHX3 LIM-Homeodomain Transcription Factor
Endocrinology, 2004Co-Authors: Brooke E. West, Kyle W Sloop, Jesse J. Savage, Stephanie C Colvin, Gretchen E. Parker, Parinda Kiratipranon, Katherine S. Toomey, Lisa R. Beach, Simon J. RhodesAbstract:FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIMhomeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH -subunit promoter, but not the proximal LH promoter. The related LHX4 mammalian transcription factor can also induce FSH promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein
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an isoform specific inhibitory domain regulates the lhx3 lim homeodomain factor holoprotein and the production of a functional alternate translation form
Journal of Biological Chemistry, 2001Co-Authors: Kyle W Sloop, Conor J Dwyer, Simon J. RhodesAbstract:Abstract The LHX3 LIM homeodomain transcription factor is required for pituitary development and motor neuron specification. TheLhx3 gene encodes two isoforms, LHX3a and LHX3b, that differ in their amino-terminal sequences. Humans and mice with defective Lhx3 genes are deficient in gonadotrope, lactotrope, somatotrope, and thyrotrope pituitary cells. We show that, whereas Lhx3b is highly expressed in theseLhx3-dependent cell types, high levels ofLhx3a expression are restricted to α glycoprotein subunit-expressing thyrotropes and gonadotropes. Cross-species comparison reveals the LHX3b-specific domain is more conserved than the LHX3a-specific domain. We demonstrate that the LHX3b-specific domain is a transferable inhibitor that reduces gene activation and DNA binding by homeodomain proteins. In addition, we identify a novel LHX3 protein (M2-LHX3) and determine that this molecule is generated by an internal translation initiation codon. The LHX3a- and LHX3b-specific coding sequences regulate differential usage of this internal start codon. Further, we identify the major activation domain of LHX3 in the carboxyl terminus of the molecule. M2-LHX3 is active because it retains this domain and binds DNA better than LHX3a or LHX3b. Other LIM homeodomain genes, including Lhx4, generate similar truncated proteins. These studies describe how transcriptional regulatory genes can generate multiple functional proteins.
Tuomas O Kilpelainen - One of the best experts on this subject based on the ideXlab platform.
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multi ancestry study of blood lipid levels identifies four loci interacting with physical activity
Nature Communications, 2019Co-Authors: Tuomas O Kilpelainen, Amy R Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W Winkler, Hermina Jakupovic, Daniel I ChasmanAbstract:Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.