The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Leslie G. Biesecker - One of the best experts on this subject based on the ideXlab platform.
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genitourinary malformations as a feature of the Pallister Hall Syndrome
Clinical Dysmorphology, 2006Co-Authors: Emma Mccann, Alan Fryer, Ross J Craigie, Colin Baillie, Muhammed E Baath, Andrew Selby, Leslie G. BieseckerAbstract:Pallister-Hall and McKusick-Kaufman Syndromes are developmental disorders with well defined phenotypes, distinct loci and different patterns of inheritance. The clinical features can overlap and may cause diagnostic difficulty, particularly if complex genitourinary malformations are present. A case is presented with features of both Syndromes but in which a GLI3 mutation has been identified. A literature review of similar cases is presented and it is proposed that these cases probably represent the Pallister-Hall Syndrome. A detailed abdominal and perineal examination should be considered in all female patients with the Pallister-Hall Syndrome, looking for associated genitourinary anomalies. Conversely, all girls with features suggestive of McKusick-Kaufman Syndrome require neuroimaging to look for features of the Pallister-Hall Syndrome. The correct diagnosis is important so that the patient and the family may receive appropriate management. It also allows provision for an accurate recurrence risk.
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hypothalamic hamartomas and seizures distinct natural history of isolated and Pallister Hall Syndrome cases
Epilepsia, 2005Co-Authors: Eilis A Boudreau, Nicholas J Patronas, Penelope Feuillan, Joyce T Turner, Kore Liow, Carol Frattali, Edith Wiggs, Susumu Sato, Athos Patsalides, Leslie G. BieseckerAbstract:Summary: Purpose: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall Syndrome (PHS), have a more benign course. Methods: Thirty-seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems. Results: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH. Conclusions: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.
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psychiatric and neuropsychological characterization of Pallister Hall Syndrome
Clinical Genetics, 2004Co-Authors: Amin Azzam, D M Lerner, Kathryn F Peters, E Wiggs, D L Rosenstein, Leslie G. BieseckerAbstract:Pallister-Hall Syndrome (PHS) is a rare, single-gene, malformation Syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The Syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic Syndromes is discussed in light of this negative result.
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gonadal mosaicism in severe Pallister Hall Syndrome
American Journal of Medical Genetics Part A, 2004Co-Authors: Jennifer J Johnston, E Wiggs, Joyce T Turner, Eilis A Boudreau, William H Theodore, Leslie G. BieseckerAbstract:Pallister-Hall Syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.
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overlap of piv Syndrome vacterl and Pallister Hall Syndrome clinical and molecular analysis
Clinical Genetics, 2001Co-Authors: Christina Killoran, Margaret H. Abbott, Victor A Mckusick, Leslie G. BieseckerAbstract:The polydactyly, imperforate anus, vertebral anomalies Syndrome (PIV, OMIM 174100) was determined as a distinct Syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall Syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another Syndrome with overlapping malformations.
Norman D. Rosenblum - One of the best experts on this subject based on the ideXlab platform.
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urogenital development in Pallister Hall Syndrome is disrupted in a cell lineage specific manner by constitutive expression of gli3 repressor
Human Molecular Genetics, 2016Co-Authors: Joshua Blake, Jason E. Cain, Norman D. RosenblumAbstract:Pallister-Hall Syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.
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GLI3 repressor controls functional development of the mouse ureter
Journal of Clinical Investigation, 2011Co-Authors: Jason E. Cain, Epshita Islam, Joshua Blake, Fiona Haxho, Norman D. RosenblumAbstract:Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall Syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation–3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.
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gli3 repressor controls nephron number via regulation of wnt11 and ret in ureteric tip cells
PLOS ONE, 2009Co-Authors: Jason E. Cain, Epshita Islam, Fiona Haxho, Lin Chen, Darren Bridgewater, Erica Nieuwenhuis, Chichung Hui, Norman D. RosenblumAbstract:Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1−/−UB mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3−/− mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1−/−UB mice. Indeed, constitutive expression of GLI3 repressor via the Gli3Δ699 allele in Ptc1−/−UB mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret.
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GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells.
Public Library of Science (PLoS), 2009Co-Authors: Jason E. Cain, Epshita Islam, Fiona Haxho, Lin Chen, Darren Bridgewater, Erica Nieuwenhuis, Chichung Hui, Norman D. RosenblumAbstract:Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1(-/-UB) mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3(-/-) mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1(-/-UB) mice. Indeed, constitutive expression of GLI3 repressor via the Gli3(Delta699) allele in Ptc1(-/-UB) mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret
John M. Graham - One of the best experts on this subject based on the ideXlab platform.
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linkage mapping and phenotypic analysis of autosomal dominant Pallister Hall Syndrome
Journal of Medical Genetics, 1997Co-Authors: Seongman Kang, Alejandro A. Schäffer, Jeffrey C. Allen, Carol L. Clericuzio, Theresa A. Grebe, John M. Graham, Nicholas J Patronas, Frank G Ondrey, Eric D Green, Margaret H. AbbottAbstract:Pallister-Hall Syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the Syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly Syndrome. Although Greig cephalopolysyndactyly Syndrome has some phenotypic overlap with Pallister-Hall Syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall Syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall Syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.
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GLI3 frameshift mutations cause autosomal dominant Pallister-Hall Syndrome
Nature genetics, 1997Co-Authors: Seongman Kang, Ann Haskins Olney, John M. Graham, Leslie G. BieseckerAbstract:Pallister-Hall Syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations1,2. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall Syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)). co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene3. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly Syndrome (GCPS; M175700)4–6 although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct7,8. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3′ of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.
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Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall Syndrome.
Journal of medical genetics, 1996Co-Authors: Leslie G. Biesecker, Seongman Kang, Alejandro A. Schäffer, Margaret H. Abbott, Richard I. Kelley, Jeffrey C. Allen, Carol L. Clericuzio, Theresa A. Grebe, Ann Haskins Olney, John M. GrahamAbstract:Pallister-Hall Syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz Syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz Syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz Syndrome are not allelic variants of a single locus.
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report from the workshop on Pallister Hall Syndrome and related phenotypes
American Journal of Medical Genetics, 1996Co-Authors: Leslie G. Biesecker, Seongman Kang, Margaret H. Abbott, Jeffrey C. Allen, Carol L. Clericuzio, Ann Haskins Olney, John M. Graham, Judith G Hall, Penelope Feuillan, Daniel R LeftonAbstract:A one day workshop was convened on the NIH campus on March 1, 1996, in Bethesda, Maryland to discuss emerging clinical and molecular information on Pallister-Hall Syndrome (PHS) and related disorders. PHS is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations. The goals of the meeting were to update participants in the latest clinical and research findings in the disorder, review the history and evolution of the understanding of the phenotype, determine diagnostic criteria for PHS, and make recommendations for clinical evaluation of individuals affected by PHS. These topics were addressed by several speakers and data were displayed from several of the large pedigrees of autosomal dominant PHS. 37 refs., 4 tabs.
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Pallister Hall Syndrome
Journal of Medical Genetics, 1996Co-Authors: Leslie G. Biesecker, John M. GrahamAbstract:DrBiesecker. ASyndrome ofhypothalamic hamartoma, polydactyly, panhypopituitarism, imperforate anus, andother visceral anomalies wasdelineated by Hallandcolleagues in1980.12 ThisSyndrome hasbeenmostcommonly designated PallisterHallSyndrome (PHS)although someprefer thedesignation Hall-Pallister Syndrome to parallel theauthorship ofthatseminal description.3 Theoriginal report described six children, allofwhomweresporadic cases and diedwithsevere anomalies. Before that report, there areseveral descriptions ofchildren who mayhavehadthesamedisorder although the authors didnotdescribe itasadistinct Syndromeanddidnotthoroughly describe the anomalies.45 Because thecasesofHalletall2 weresevere andsporadic, theauthors were cautious intheir speculation abouttherange ofseverity thatmightbeassociated withthis disorder andits inheritance pattern. Therehave beennumerous casereports described inthe 15yearsfollowing thereport byHalletal.'2 Thesecases present apicture ofanevolving phenotype withsuccessively milder cases being assigned thatdiagnosis. Inthissummarywe Major manifestations ofPallister-Hall Syndrome Major mianifestations Frequetncy*
Jason E. Cain - One of the best experts on this subject based on the ideXlab platform.
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urogenital development in Pallister Hall Syndrome is disrupted in a cell lineage specific manner by constitutive expression of gli3 repressor
Human Molecular Genetics, 2016Co-Authors: Joshua Blake, Jason E. Cain, Norman D. RosenblumAbstract:Pallister-Hall Syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.
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GLI3 repressor controls functional development of the mouse ureter
Journal of Clinical Investigation, 2011Co-Authors: Jason E. Cain, Epshita Islam, Joshua Blake, Fiona Haxho, Norman D. RosenblumAbstract:Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall Syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation–3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.
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gli3 repressor controls nephron number via regulation of wnt11 and ret in ureteric tip cells
PLOS ONE, 2009Co-Authors: Jason E. Cain, Epshita Islam, Fiona Haxho, Lin Chen, Darren Bridgewater, Erica Nieuwenhuis, Chichung Hui, Norman D. RosenblumAbstract:Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1−/−UB mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3−/− mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1−/−UB mice. Indeed, constitutive expression of GLI3 repressor via the Gli3Δ699 allele in Ptc1−/−UB mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret.
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GLI3 repressor controls nephron number via regulation of Wnt11 and Ret in ureteric tip cells.
Public Library of Science (PLoS), 2009Co-Authors: Jason E. Cain, Epshita Islam, Fiona Haxho, Lin Chen, Darren Bridgewater, Erica Nieuwenhuis, Chichung Hui, Norman D. RosenblumAbstract:Truncating GLI3 mutations in Pallister-Hall Syndrome with renal malformation suggests a requirement for Hedgehog signaling during renal development. HH-dependent signaling increases levels of GLI transcriptional activators and decreases processing of GLI3 to a shorter transcriptional repressor. Previously, we showed that Shh-deficiency interrupts early inductive events during renal development in a manner dependent on GLI3 repressor. Here we identify a novel function for GLI3 repressor in controlling nephron number. During renal morphogenesis, HH signaling activity, assayed by expression of Ptc1-lacZ, is localized to ureteric cells of the medulla, but is undetectable in the cortex. Targeted inactivation of Smo, the HH effector, in the ureteric cell lineage causes no detectable abnormality in renal morphogenesis. The functional significance of absent HH signaling activity in cortical ureteric cells was determined by targeted deletion of Ptc1, the SMO inhibitor, in the ureteric cell lineage. Ptc1(-/-UB) mice demonstrate ectopic Ptc1-lacZ expression in ureteric branch tips and renal hypoplasia characterized by reduced kidney size and a paucity of mature and intermediate nephrogenic structures. Ureteric tip cells are remarkable for abnormal morphology and impaired expression of Ret and Wnt11, markers of tip cell differentiation. A finding of renal hypoplasia in Gli3(-/-) mice suggests a pathogenic role for reduced GLI3 repressor in the Ptc1(-/-UB) mice. Indeed, constitutive expression of GLI3 repressor via the Gli3(Delta699) allele in Ptc1(-/-UB) mice restores the normal pattern of HH signaling, and expression of Ret and Wnt11 and rescued the renal phenotype. Thus, GLI3 repressor controls nephron number by regulating ureteric tip cell expression of Wnt11 and Ret
Seongman Kang - One of the best experts on this subject based on the ideXlab platform.
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linkage mapping and phenotypic analysis of autosomal dominant Pallister Hall Syndrome
Journal of Medical Genetics, 1997Co-Authors: Seongman Kang, Alejandro A. Schäffer, Jeffrey C. Allen, Carol L. Clericuzio, Theresa A. Grebe, John M. Graham, Nicholas J Patronas, Frank G Ondrey, Eric D Green, Margaret H. AbbottAbstract:Pallister-Hall Syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the Syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly Syndrome. Although Greig cephalopolysyndactyly Syndrome has some phenotypic overlap with Pallister-Hall Syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall Syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall Syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.
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GLI3 frameshift mutations cause autosomal dominant Pallister-Hall Syndrome
Nature genetics, 1997Co-Authors: Seongman Kang, Ann Haskins Olney, John M. Graham, Leslie G. BieseckerAbstract:Pallister-Hall Syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations1,2. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall Syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)). co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene3. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly Syndrome (GCPS; M175700)4–6 although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct7,8. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3′ of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.
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Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall Syndrome.
Journal of medical genetics, 1996Co-Authors: Leslie G. Biesecker, Seongman Kang, Alejandro A. Schäffer, Margaret H. Abbott, Richard I. Kelley, Jeffrey C. Allen, Carol L. Clericuzio, Theresa A. Grebe, Ann Haskins Olney, John M. GrahamAbstract:Pallister-Hall Syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz Syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz Syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz Syndrome are not allelic variants of a single locus.
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report from the workshop on Pallister Hall Syndrome and related phenotypes
American Journal of Medical Genetics, 1996Co-Authors: Leslie G. Biesecker, Seongman Kang, Margaret H. Abbott, Jeffrey C. Allen, Carol L. Clericuzio, Ann Haskins Olney, John M. Graham, Judith G Hall, Penelope Feuillan, Daniel R LeftonAbstract:A one day workshop was convened on the NIH campus on March 1, 1996, in Bethesda, Maryland to discuss emerging clinical and molecular information on Pallister-Hall Syndrome (PHS) and related disorders. PHS is a pleiotropic autosomal dominant disorder comprising hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations. The goals of the meeting were to update participants in the latest clinical and research findings in the disorder, review the history and evolution of the understanding of the phenotype, determine diagnostic criteria for PHS, and make recommendations for clinical evaluation of individuals affected by PHS. These topics were addressed by several speakers and data were displayed from several of the large pedigrees of autosomal dominant PHS. 37 refs., 4 tabs.
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clinical and genetic analysis of Pallister Hall Syndrome 470
Pediatric Research, 1996Co-Authors: Leslie G. Biesecker, Seongman Kang, Jeffrey C. Allen, Carol L. Clericuzio, Theresa A. Grebe, Ann Haskins Olney, John M. GrahamAbstract:Typical Pallister-Hall Syndrome consists of hypothalamic hamartoma with or without pituitary dysplasia or dysfunction, polydactyly, imperforate anus, and other anomalies of the respiratory, renal and cardiac systems. It was originally described in 6 sporadic cases, all of whom died in the neonatal period. Subsequently, we and others have evaluated several cases of families affected with a milder variation of this disorder, which is inherited in an autosomal dominant pattern. The three families (families A, B & C) summarized in this report include families with 4, 12, and 22 affected members, respectively. All of the affecteds in the pedigrees have polydactyly, which is variable in the number of limbs affected (2-4) and in the type of polydactyly (postaxial or central). MRI scans of the brain have been performed on 14 patients and 12 of those showed hypothalamic hamartoma +/- pituitary dysplasia. One subject had an autopsy performed for forensic reasons and this examination revealed a hypothalamic hamartoma. Pituitary dysfunction is not seen in these mildly affected families. Among these three families, there are 1, 4, and 10 obligate heterozygotes, respectively. Among these 15 obligate heterozygotes, all 15 show some signs of the disorder and all of them have polydactyly. All but one of the obligate heterozygotes have a hypothalamic hamartoma on MRI examination. In addition to these clinical studies, we have performed a genetic analysis to test for linkage to regions or candidate genes that have been suggested on the basis of clinical findings (overlap with Smith-Lemli-Opitz Syndrome (Donnai AJMG 38:741, 1987), a family history of proximal symphalangism (family B), and a patient with PHS-like findings and an unbalanced translocation (Kuller et al 43:746, 1992)). Linkage analysis demonstrates that all of these regions are excluded by LOD scores of <-2.0. We conclude that familial PHS is an autosomal dominant disorder with high penetrance and variable expressivity. Genome-wide linkage studies are under way.