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Lee S Weinstein - One of the best experts on this subject based on the ideXlab platform.
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pseudohypoparathyroidism type 1a Pseudopseudohypoparathyroidism and albright hereditary osteodystrophy
2015Co-Authors: Lee S WeinsteinAbstract:Albright hereditary osteodystrophy (AHO) is a congenital disorder caused by heterozygous loss-of-function mutations of the GNAS gene encoding Gsα, the ubiquitously expressed G protein α-subunit that is required for intracellular cAMP generation in response to hormones and other extracellular signals. AHO patients develop short stature, brachydactyly, subcutaneous ossifications, and, in some cases, neurocognitive impairment. Due to genomic imprinting of GNAS, mutations on the maternal allele also lead to multihormone resistance and early-onset obesity, a condition known as pseudohypoparathyroidism type 1a. In contrast paternal mutations only lead to AHO, also known as Pseudopseudohypoparathyroidism. In some instances, the same Gsα mutations are associated with a more severe form of ectopic ossification known as progressive osseous heteroplasia.
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albright hereditary osteodystrophy current progress and new frontiers
Seminars in Arthritis and Rheumatism, 2013Co-Authors: Emily L Germainlee, Lee S WeinsteinAbstract:Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly, brachymetacarpia, short stature, subcutaneous ossifications, and dental abnormalities. This disorder is caused by heterozygous, inactivating mutations in GNAS , the gene encoding the alpha chain of the heterotrimeric G protein, Gs, that couples with receptors for many hormones and neurotransmitters for the activation of adenylyl cyclase. Transcripts encoding Gαs are preferentially expressed from the maternally inherited allele in the renal proximal tubule, thyroid, gonad, and pituitary. AHO patients who have GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (including PTH, TSH, gonadotropins, and GHRH) as well as obesity and cognitive deficits. This condition is termed pseudohypoparathyroidism type Ia (PHP Ia) and is due to tissue-specific paternal imprinting. Conversely, patients with AHO and GNAS mutations on their paternally inherited alleles have no evidence of hormonal resistance, are typically not obese, and cognitive function may be normal. This condition is termed Pseudopseudohypoparathyroidism (PPHP). Current knowledge as well as the research in progress in both humans and mouse models regarding the major clinical problems in AHO will be reviewed. Dr. Germain-Lee will focus on her past and current research involving clinical trials with growth hormone in patients with AHO, as well as her research on the heterotopic ossifications that develop in this condition, which she is examining through the use of a mouse model. Her research on the etiology and mechanisms underlying the formation of the heterotopic ossifications has broader implications in terms of the potential to understand more about the mechanisms of osteogenesis overall. In addition, Dr. Germain-Lee will discuss her clinical findings related to the severe obesity in pseudohypoparathyroidism type Ia; this severe obesity is not present in Pseudopseudohypoparathyroidism. Dr. Weinstein will discuss his basic science research on metabolism and obesity in AHO, which is based on his studies of his mouse models of this condition. In addition, he will discuss his current ongoing clinical studies of obesity and metabolism in AHO.
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body mass index differences in pseudohypoparathyroidism type 1a versus Pseudopseudohypoparathyroidism may implicate paternal imprinting of gαs in the development of human obesity
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Dominique N Long, Michael A. Levine, Lee S Weinstein, Sarah Mcguire, Emily L GermainleeAbstract:Context: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein α-subunit Gαs. Because Gαs is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [Pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions. Setting: This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health. Patients: Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied. Main Outcome Measures: Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores. Results: Patients with PHP1a had s...
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the stimulatory g protein α subunit gsα is imprinted in human thyroid glands implications for thyroid function in pseudohypoparathyroidism types 1a and 1b
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Beth Erlichman, Lee S WeinsteinAbstract:The stimulatory G protein α-subunit Gsα couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous Gsα null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of Gsα in specific hormone targets could explain this observation. Using hot-stop PCR analysis on total RNA from six normal human thyroid specimens, we showed that the majority of the Gsα mRNA (72 ± 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal Gsα null mutations (PHP1A) and the absence of TSH resistance in patients with paternal Gsα mutations (Pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the Gsα gene resulting in both alleles having a paternal epigenotype, which would lead t...
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Identification of Two Novel Deletion Mutations within the Gsα Gene (GNAS1) in Albright Hereditary Osteodystrophy1
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Volker Schuster, Klaus Kruse, Carol L. Clericuzio, Lee S WeinsteinAbstract:Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [Pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues[ pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gsα, the α-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gsα gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and ...
H. G. Dörr - One of the best experts on this subject based on the ideXlab platform.
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Stimulatory guanine nucleotide binding protein subunit 1 mutation in two siblings with pseudohypoparathyroidism type 1a and mother with Pseudopseudohypoparathyroidism
European Journal of Pediatrics, 1999Co-Authors: U. Walden, R. Weissörtel, Z. Corria, L. Weinstein, K. Kruse, H. G. DörrAbstract:Pseudohypoparathyroidism (PHP) type 1a is characterized by multihormone resistance and a constellation of somatic features referred to as Albright hereditary osteodystrophy. Several mutations in the gene coding for the Gsα subunit (GNAS1) have been described. Clinical symptoms are heterogeneous and initially laboratory parameters may be normal. We identified a 4 base pair deletion within GNAS1 in two affected siblings with PHP type 1a and their mother with presumed pseudo PHP. The female proband was diagnosed after an episode of apnoea and seizures. The younger brother was asymptomatic during infancy and had normal plasma parameters. PHP was diagnosed at the age of 4.4 years. Regular check-ups of siblings in families with index cases are therefore important. Molecular genetic analyses or biochemical screening for stimulatory guanine nucleotide binding protein defects should be performed. Conclusion Different symptoms may be seen in patients with the same mutation causing pseudohypoparathyroidism or Pseudopseudohypoparathyroidism. Therefore, clinical and biochemical investigations should be performed in all family members with an index patient.
U. Walden - One of the best experts on this subject based on the ideXlab platform.
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Stimulatory guanine nucleotide binding protein subunit 1 mutation in two siblings with pseudohypoparathyroidism type 1a and mother with Pseudopseudohypoparathyroidism
European Journal of Pediatrics, 1999Co-Authors: U. Walden, R. Weissörtel, Z. Corria, L. Weinstein, K. Kruse, H. G. DörrAbstract:Pseudohypoparathyroidism (PHP) type 1a is characterized by multihormone resistance and a constellation of somatic features referred to as Albright hereditary osteodystrophy. Several mutations in the gene coding for the Gsα subunit (GNAS1) have been described. Clinical symptoms are heterogeneous and initially laboratory parameters may be normal. We identified a 4 base pair deletion within GNAS1 in two affected siblings with PHP type 1a and their mother with presumed pseudo PHP. The female proband was diagnosed after an episode of apnoea and seizures. The younger brother was asymptomatic during infancy and had normal plasma parameters. PHP was diagnosed at the age of 4.4 years. Regular check-ups of siblings in families with index cases are therefore important. Molecular genetic analyses or biochemical screening for stimulatory guanine nucleotide binding protein defects should be performed. Conclusion Different symptoms may be seen in patients with the same mutation causing pseudohypoparathyroidism or Pseudopseudohypoparathyroidism. Therefore, clinical and biochemical investigations should be performed in all family members with an index patient.
Seyed Masoud Arzaghi - One of the best experts on this subject based on the ideXlab platform.
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A patient with features of albright hereditory osteodystrophy and unusual neuropsychiatric findings without coding Gsalpha mutations
Journal of diabetes and metabolic disorders, 2014Co-Authors: Shirin Hasani-ranjbar, Zahra Jouyandeh, Mahsa M. Amoli, Akbar Soltani, Seyed Masoud ArzaghiAbstract:Background Pseudohypoparathyroidism(PHP) is a heterogeneous group of rare metabolic disorders characterized by hypocalcemia and hyperphosphatemia resulting from PTH resistance. Different forms of PHP have been reported based on biochemical and clinical manifestation and genetic findings. Most of these forms are caused by defects in GNAS, an imprinted gene locus with multiple subunits. We reported a 12- year- old girl with unusual clinical manifestations of Pseudopseudohypoparathyroidism(PPHP).
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A patient with features of albright hereditory osteodystrophy and unusual neuropsychiatric findings without coding Gsalpha mutations
Journal of Diabetes & Metabolic Disorders, 2014Co-Authors: Shirin Hasani-ranjbar, Zahra Jouyandeh, Mahsa M. Amoli, Akbar Soltani, Seyed Masoud ArzaghiAbstract:Background Pseudohypoparathyroidism(PHP) is a heterogeneous group of rare metabolic disorders characterized by hypocalcemia and hyperphosphatemia resulting from PTH resistance. Different forms of PHP have been reported based on biochemical and clinical manifestation and genetic findings. Most of these forms are caused by defects in GNAS, an imprinted gene locus with multiple subunits. We reported a 12- year- old girl with unusual clinical manifestations of Pseudopseudohypoparathyroidism(PPHP). Methods After clinical and biochemical evaluations, the patients’ genomic DNA was isolated from peripheral blood leukocytes using salting out method. The whole coding sequences of GNAS gene including 13 exons were amplified by PCR. Quantitative PCR reactions were performed too. Findings We described a 12- year- old girl with Albright Hereditory osteodystrophy (AHO) phenotype, poor school performance, some abnormal movements, TSH resistance with normal serum calcium and phosphorus levels and normal Gsα bioactivity with no mutation in GNAS exons. Unusual neuropsychiatric findings in this patient were compatible with Asperger syndrome. Conclusions According to our findings this patient could not be categorized in any of PHP subgroups. Identifying of such individuals may be useful to discover different genetic patterns in pseudohypoparathyroidism and Pseudopseudohypoparathyroidism. It is important to identify patients in whom PHP is caused by novel GNAS mutations, as careful investigations of these findings will likely further our knowledge of this complex and this unique disorder. In addition this case presented with unusual neuropsychiatric findings which has not been reported up to now.
Michael A. Levine - One of the best experts on this subject based on the ideXlab platform.
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Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy
2016Co-Authors: David L. Huso, Michael A. Levine, Sarah Edie, William Schwindinger, Yingli Wang, Emily L. Germain-leeAbstract:Albright hereditary osteodystrophy (AHO) is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO) cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the a-subunit of the stimulatory G protein (Gas). When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a). When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed Pseudopseudohypoparathyroidism (PPHP). Mice with targeted disruption of exon 1 of Gnas (GnasE12/+) replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet bee
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body mass index differences in pseudohypoparathyroidism type 1a versus Pseudopseudohypoparathyroidism may implicate paternal imprinting of gαs in the development of human obesity
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Dominique N Long, Michael A. Levine, Lee S Weinstein, Sarah Mcguire, Emily L GermainleeAbstract:Context: Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein α-subunit Gαs. Because Gαs is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [Pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions. Setting: This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health. Patients: Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied. Main Outcome Measures: Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores. Results: Patients with PHP1a had s...
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Olfactory Dysfunction in Type I Pseudohypoparathyroidism: Dissociation from Gsα Protein Deficiency1
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Richard L. Doty, Michael A. Levine, Arnold M. Moses, Alberto D. Fernandez, Donald A. MckeownAbstract:The discovery of variably decreased olfactory ability in Type Ia pseudohypoparathyroidism (PHP), a syndrome in which generalized hormone resistance is associated with deficiency of the alpha chain of the stimulatory guanine nucleotide-binding protein (Gsα) of adenylyl cyclase, has been used to support the hypothesis that Gsα plays a major role in human olfactory transduction. However, only a limited number of olfactory tests have been administered to such patients, and these patients have other problems that might cause or contribute to their olfactory dysfunction, including an unusual constellation of skeletal and developmental deficits termed Albright hereditary osteodystrophy (AHO). In this study, we administered tests of odor detection, identification, and memory to (i) 13 patients with Type Ia PHP; (ii) 8 patients with Type Ib PHP; (iii) 7 patients with Pseudopseudohypoparathyroidism (PPHP); and (iv) 3 sets of normal controls matched to these groups on the basis of age, gender, and smoking history. A...
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albright hereditary osteodystrophy and del 2 q37 3 in four unrelated individuals
American Journal of Medical Genetics, 1995Co-Authors: M C Phelan, Michael A. Levine, R C Rogers, K B Clarkson, F P Bowyer, L L Estabrooks, M C Severson, William B DobynsAbstract:Albright hereditary osteodystrophy (AHO) is a condition with characteristic physical findings (short stature, obesity, round face, brachydactyly) but variable biochemical changes (pseudohypoparathyroidism, Pseudopseudohypoparathyroidism). Most patients with AHO have decreased activity of the guanine nucleotide-binding protein (Gs protein) that stimulates adenylyl cyclase. The gene encoding the α subunit of the Gs protein (GNAS1) has been mapped to the long arm of chromosome 20. We describe 4 unrelated individuals with apparent AHO, associated with small terminal deletions of chromosome 2. All 4 patients had normal serum calcium levels consistent with Pseudopseudohypoparathyroidism. Del(2)(q37) is the first consistent karyotypic abnormality that has been documented in AHO [Phelan et al., 1993: Am J Hum Genet 53:484]. The finding of the same small terminal deletion in 4 unrelated individuals with a similar phenotype suggests that a gene locus in the 2q37 region is important in the pathogenesis of Albright syndrome. The association of Albright syndrome and the GNAS1 locus on chromosome 20 is well documented. The observation of a second potential disease locus on chromosome 2 may help explain the heterogeneity observed in this disorder. © 1995 Wiley-Liss, Inc.
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Immunochemical Analysis of the α-Subunit of the Stimulatory G-Protein of Adenylyl Cyclase in Patients with Albright's Hereditary Osteodystrophy*
The Journal of Clinical Endocrinology and Metabolism, 1990Co-Authors: Jennifer L. Patten, Michael A. LevineAbstract:Albright's hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterized by an unusual phenotypic appearance and reduced biological activity of the asubunit of the stimulatory G-protein of adenylyl cyclase (G8α). In most AHO patients deficient G8α activity is associated with generalized target organ resistance to hormones that act via stimulation of adenylyl cyclase. This form of the disorder is termed pseudohypoparathyroidism type la (PHP Ia). By contrast, other patients with G8α deficiency fail to demonstrate clinical evidence of hormone resistance and are considered to have the related disorder Pseudopseudohypoparathyroidism (pseudoPHP). Previous studies demonstrating deficient G8α bioactivity in cell membranes from patients with AHO used functional assays that were unable to distinguish between reduced amounts of normal G8α protein and normal amounts of defective G8α protein. In the present study we used specific G8α antisera to analyze immunoactive G8α protein in erythrocyte and fib...
