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Michael A Levine - One of the best experts on this subject based on the ideXlab platform.
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an update on the clinical and molecular characteristics of Pseudohypoparathyroidism
Current Opinion in Endocrinology Diabetes and Obesity, 2012Co-Authors: Michael A LevineAbstract:Purpose of reviewTo provide the reader with a review of contemporary literature describing the evolving understanding of the molecular pathobiology of Pseudohypoparathyroidism (PHP).Recent findingsThe features of PHP type 1 reflect imprinting of the GNAS gene, which encodes the α subunit of the hete
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Pseudohypoparathyroidism with osteitis fibrosa cystica direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone
Journal of Bone and Mineral Research, 2009Co-Authors: T M Murray, Minmin Wong, James P Waddell, Robert Mcbroom, Fred Rosen, Michael A LevineAbstract:: A young girl had tibial osteotomies at age 14 for genu valgum and then had recurrent tibial cysts over a number of years. Hypocalcemia and hyperphosphatemia were first noted at age 21. The diagnosis of Pseudohypoparathyroidism was made at age 28, when elevated plasma PTH was detected. Clinical and biochemical features, including a PTH response test and assay of RBC Gs, established the diagnosis of Pseudohypoparathyroidism type 1b. Failure to suppress plasma PTH with vitamin D therapy led to an exacerbation of her cystic bone disease; there were widespread lytic lesions radiologically, most of which took up [99mTc]diphosphonate on bone scan. Microradioscopy revealed evidence of resorption of phalangeal tufts. Bone biopsy showed osteitis fibrosa cystica. During an orthopedic procedure, trabecular bone fragments were taken from her right humerus, and bone-derived cells cultured using an explant technique. The cultured cells were osteoblast-like in morphology, fully responsive to PTH, cholera toxin, forskolin, and PGE1 in vitro, and had an alkaline phosphatase and osteocalcin response to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Following this examination of skeletal responsiveness, attempts were made to suppress the elevated plasma PTH levels and symptomatic bone disease by optimizing therapy with oral 1,25-(OH)2D3. When bone pain associated with the cystic bone disease failed to resolve, the patient underwent total parathyroidectomy, following which the bone pain gradually resolved. This is the first direct demonstration of PTH responsiveness in cultured bone cells in the syndrome of Pseudohypoparathyroidism with osteitis fibrosa cystica.
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selective resistance to parathyroid hormone caused by a novel uncoupling mutation in the carboxyl terminus of g alpha s a cause of Pseudohypoparathyroidism type ib
Journal of Biological Chemistry, 2001Co-Authors: Weii Wu, William F Schwindinger, Luis F Aparicio, Michael A LevineAbstract:Abstract Gs is a heterotrimeric (α, β, and γ chains) G protein that couples heptahelical plasma membrane receptors to stimulation of adenylyl cyclase. Inactivation of one GNAS1 gene allele encoding the α chain of Gs (Gαs) causes Pseudohypoparathyroidism type Ia. Affected subjects have resistance to parathyroid hormone (PTH) and other hormones that activate adenylyl cyclase plus somatic features termed Albright hereditary osteodystrophy. By contrast, subjects with Pseudohypoparathyroidism type Ib have hormone resistance that is limited to PTH and lack Albright hereditary osteodystrophy. The molecular basis for Pseudohypoparathyroidism type Ib is unknown. We analyzed theGNAS1 gene for mutations using polymerase chain reaction to amplify genomic DNA from three brothers with Pseudohypoparathyroidism type Ib. We identified a novel heterozygous 3-base pair deletion causing loss of isoleucine 382 in the three affected boys and their clinically unaffected mother and maternal grandfather. This mutation was absent in other family members and 15 additional unrelated subjects with Pseudohypoparathyroidism type Ib. To characterize the signaling properties of the mutant Gαs, we used site-directed mutagenesis to introduce the isoleucine 382 deletion into a wild type Gαs cDNA, transfected HEK293 cells with either wild type or mutant Gαs cDNA, plus cDNAs encoding heptahelical receptors for PTH, thyrotropic hormone, or luteinizing hormone, and we measured cAMP production in response to hormone stimulation. The mutant Gαs protein was unable to interact with the receptor for PTH but showed normal coupling to the other coexpressed heptahelical receptors. These results provide evidence of selective uncoupling of the mutant Gαs from PTH receptors and explain PTH-specific hormone resistance in these three brothers with Pseudohypoparathyroidism type Ib. The absence of PTH resistance in the mother and maternal grandfather who carry the same mutation is consistent with current models of paternal imprinting of the GNAS1 gene.
Giovanna Mantovani - One of the best experts on this subject based on the ideXlab platform.
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Pseudohypoparathyroidism and gsα camp linked disorders current view and open issues
Nature Reviews Endocrinology, 2016Co-Authors: Giovanna Mantovani, Anna Spada, Francesca ElliAbstract:Differential diagnosis between Pseudohypoparathyroidism and related disorders of disrupted Gsα–cAMP signalling is a challenge for endocrinologists due to shared clinical and molecular characteristics. Here, Giovanna Mantovani and colleagues discuss both the current understanding and future challenges for the clinical and molecular diagnosis, classification and treatment of Pseudohypoparathyroidism and related disorders.
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genome wide dna methylation analysis of Pseudohypoparathyroidism patients with gnas imprinting defects
Clinical Epigenetics, 2016Co-Authors: Anne Rochtus, Francesca Elli, Giovanna Mantovani, Alejandro Martintrujillo, Benedetta Izzi, Intza Garin, Agnes Linglart, Guiomar Perez De Nanclares, Suzanne Thiele, Brigitte DecallonneAbstract:Background Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis.
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autosomal dominant Pseudohypoparathyroidism type ib a novel inherited deletion ablating stx16 causes loss of imprinting at the a b dmr
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesca Elli, Paolo Bordogna, Paolo Beckpeccoz, Anna Spada, Luisa De Sanctis, Erika Peverelli, Barbara Pivetta, Gianmaria Miolo, Giovanna MantovaniAbstract:Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant Pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods. Objective: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underl...
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Pseudohypoparathyroidism type ia and pseudo Pseudohypoparathyroidism the growing spectrum of gnas inactivating mutations
Human Mutation, 2013Co-Authors: Francesca Elli, Luisa Desanctis, Barbara Ceoloni, Anna Maria Barbieri, Paolo Bordogna, Paolo Beckpeccoz, Anna Spada, Giovanna MantovaniAbstract:: Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP-Ia), when maternally inherited, or pseudo-pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60-70% of affected subjects, most patients/families harbor private mutations and no genotype-phenotype correlation has been found to date. We investigated Gsα-coding GNAS exons in a large panel of PHP-Ia-PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, we identified 15 novel mutations in 19 patients. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS-locus-specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.
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Pseudohypoparathyroidism diagnosis and treatment
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Giovanna MantovaniAbstract:Context: The term Pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of various hormones (primarily PTH) that activate cAMP-dependent pathways via Gsα protein. The two main subtypes of PHP, PHP type Ia, and Ib (PHP-Ia, PHP-Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsα and other translated and untranslated products. Evidence acquisition: A PubMed search was used to identify the available studies (main query terms: Pseudohypoparathyroidism; Albright hereditary osteodystrophy; GNAS; GNAS1; progressive osseous heteroplasia). The most relevant studies until February 2011 have been included in the review. Evidence synthesis and conclusions: Despite the first description of this disorder dates back to 1942, recent findings indicating complex epigenetic alterations beside classical mutations at the GNAS complex gene, pointed out the limitation of the actual classification o...
Murat Bastepe - One of the best experts on this subject based on the ideXlab platform.
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GNAS Spectrum of Disorders
Current Osteoporosis Reports, 2015Co-Authors: Serap Turan, Murat BastepeAbstract:The GNAS complex locus encodes the alpha-subunit of the stimulatory G protein (Gsα), a ubiquitous signaling protein mediating the actions of many hormones, neurotransmitters, and paracrine/autocrine factors via generation of the second messenger cAMP. GNAS gives rise to other gene products, most of which exhibit exclusively monoallelic expression. In contrast, Gsα is expressed biallelically in most tissues; however, paternal Gsα expression is silenced in a small number of tissues through as-yet-poorly understood mechanisms that involve differential methylation within GNAS . Gsα-coding GNAS mutations that lead to diminished Gsα expression and/or function result in Albright’s hereditary osteodystrophy (AHO) with or without hormone resistance, i.e., Pseudohypoparathyroidism type-Ia/Ic and pseudo-Pseudohypoparathyroidism, respectively. Microdeletions that alter GNAS methylation and, thereby, diminish Gsα expression in tissues in which the paternal Gsα allele is normally silenced also cause hormone resistance, which occurs typically in the absence of AHO, a disorder termed Pseudohypoparathyroidism type-Ib. Mutations of GNAS that cause constitutive Gsα signaling are found in patients with McCune-Albright syndrome, fibrous dysplasia of bone, and different endocrine and non-endocrine tumors. Clinical features of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing. In this article, we review the pathogenesis and the phenotypes of these human diseases.
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phenotypic and molecular genetic aspects of Pseudohypoparathyroidism type ib in a greek kindred evidence for enhanced uric acid excretion due to parathyroid hormone resistance
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Elena Laspa, Harald Juppner, Murat Bastepe, Agathocles TsatsoulisAbstract:The predominant feature of Pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the α-subunit of the stimulatory G protein (Gsα). Besides PTH resistance, PHP-Ia patients have Albright’s hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright’s hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. I...
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paternal uniparental isodisomy of chromosome 20q and the resulting changes in gnas1 methylation as a plausible cause of Pseudohypoparathyroidism
American Journal of Human Genetics, 2001Co-Authors: Murat Bastepe, Andrew Lane, Harald JuppnerAbstract:Heterozygous inactivating mutations in the GNAS1 exons (20q13.3) that encode the α-subunit of the stimulatory G protein (Gsα) are found in patients with Pseudohypoparathyroidism type Ia (PHP-Ia) and in patients with pseudo-Pseudohypoparathyroidism (pPHP). However, because of paternal imprinting, resistance to parathyroid hormone (PTH)—and, sometimes, to other hormones that require Gsα signaling—develops only if the defect is inherited from a female carrier of the disease gene. An identical mode of inheritance is observed in kindreds with Pseudohypoparathyroidism type Ib (PHP-Ib), which is most likely caused by mutations in regulatory regions of the maternal GNAS1 gene that are predicted to interfere with the parent-specific methylation of this gene. We report a patient with PTH-resistant hypocalcemia and hyperphosphatemia but without evidence for Albright hereditary osteodystrophy who has paternal uniparental isodisomy of chromosome 20q and lacks the maternal-specific methylation pattern within GNAS1. Since studies in the patient’s fibroblasts did not reveal any evidence of impaired Gsα protein or activity, it appears that the loss of the maternal GNAS1 gene and the resulting epigenetic changes alone can lead to PTH resistance in the proximal renal tubules and thus lead to impaired regulation of mineral-ion homeostasis.
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the gene responsible for Pseudohypoparathyroidism type ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13 3
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Harald Juppner, Ernestina Schipani, Murat Bastepe, David E C Cole, Margaret L Lawson, Michael Mannstadt, Geoffrey N Hendy, H Plotkin, Hiroyuki Koshiyama, J D CrawfordAbstract:Hypocalcemia and hyperphosphatemia caused by parathyroid hormone (PTH)-resistance are the only discernible abnormalities in Pseudohypoparathyroidism type Ib (PHP-Ib). Because mutations in the PTH/PTH-related peptide receptor, a plausible candidate gene, had been excluded previously, we conducted a genome-wide search with four PHP-Ib kindreds and established linkage to a small telomeric region on chromosome 20q, which contains the stimulatory G protein gene. We, furthermore, showed that the genetic defect is imprinted paternally and thus is inherited in the same mode as the PTH-resistant hypocalcemia in kindreds with PHP-Ia and/or pseudo-Pseudohypoparathyroidism, two related disorders caused by different stimulatory G protein mutations.
Harald Juppner - One of the best experts on this subject based on the ideXlab platform.
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Pseudohypoparathyroidism type ib php ib pth resistant hypocalcemia and hyperphosphatemia due to abnormal gnas methylation
2015Co-Authors: Harald JuppnerAbstract:Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder characterized by PTH resistance in the proximal renal tubules, which leads to hypocalcemia, hyperphosphatemia, and an elevated serum PTH level. Resistance to other hormones that mediate their actions through G protein-coupled receptors and evidence for AHO can also be observed but are much less frequently than in Pseudohypoparathyroidism type Ia (PHP-Ia). Most variants of PHP-Ib are associated with GNAS methylation changes, thereby reducing maternal expression of the stimulatory G protein (Gsα) in few tissues, where paternal expression of this signaling protein is silenced through as-of-yet unknown mechanisms. In familial PHP-Ib cases, these epigenetic changes are caused by deletions within or upstream of GNAS. Duplication of large portions of the paternal chromosome 20q is observed in a few patients with the sporadic form of the disease, but most of these PHP-Ib cases remain undefined at the molecular level.
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phenotypic and molecular genetic aspects of Pseudohypoparathyroidism type ib in a greek kindred evidence for enhanced uric acid excretion due to parathyroid hormone resistance
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Elena Laspa, Harald Juppner, Murat Bastepe, Agathocles TsatsoulisAbstract:The predominant feature of Pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the α-subunit of the stimulatory G protein (Gsα). Besides PTH resistance, PHP-Ia patients have Albright’s hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright’s hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. I...
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paternal uniparental isodisomy of chromosome 20q and the resulting changes in gnas1 methylation as a plausible cause of Pseudohypoparathyroidism
American Journal of Human Genetics, 2001Co-Authors: Murat Bastepe, Andrew Lane, Harald JuppnerAbstract:Heterozygous inactivating mutations in the GNAS1 exons (20q13.3) that encode the α-subunit of the stimulatory G protein (Gsα) are found in patients with Pseudohypoparathyroidism type Ia (PHP-Ia) and in patients with pseudo-Pseudohypoparathyroidism (pPHP). However, because of paternal imprinting, resistance to parathyroid hormone (PTH)—and, sometimes, to other hormones that require Gsα signaling—develops only if the defect is inherited from a female carrier of the disease gene. An identical mode of inheritance is observed in kindreds with Pseudohypoparathyroidism type Ib (PHP-Ib), which is most likely caused by mutations in regulatory regions of the maternal GNAS1 gene that are predicted to interfere with the parent-specific methylation of this gene. We report a patient with PTH-resistant hypocalcemia and hyperphosphatemia but without evidence for Albright hereditary osteodystrophy who has paternal uniparental isodisomy of chromosome 20q and lacks the maternal-specific methylation pattern within GNAS1. Since studies in the patient’s fibroblasts did not reveal any evidence of impaired Gsα protein or activity, it appears that the loss of the maternal GNAS1 gene and the resulting epigenetic changes alone can lead to PTH resistance in the proximal renal tubules and thus lead to impaired regulation of mineral-ion homeostasis.
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the gene responsible for Pseudohypoparathyroidism type ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13 3
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Harald Juppner, Ernestina Schipani, Murat Bastepe, David E C Cole, Margaret L Lawson, Michael Mannstadt, Geoffrey N Hendy, H Plotkin, Hiroyuki Koshiyama, J D CrawfordAbstract:Hypocalcemia and hyperphosphatemia caused by parathyroid hormone (PTH)-resistance are the only discernible abnormalities in Pseudohypoparathyroidism type Ib (PHP-Ib). Because mutations in the PTH/PTH-related peptide receptor, a plausible candidate gene, had been excluded previously, we conducted a genome-wide search with four PHP-Ib kindreds and established linkage to a small telomeric region on chromosome 20q, which contains the stimulatory G protein gene. We, furthermore, showed that the genetic defect is imprinted paternally and thus is inherited in the same mode as the PTH-resistant hypocalcemia in kindreds with PHP-Ia and/or pseudo-Pseudohypoparathyroidism, two related disorders caused by different stimulatory G protein mutations.
Francesca Elli - One of the best experts on this subject based on the ideXlab platform.
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Pseudohypoparathyroidism and gsα camp linked disorders current view and open issues
Nature Reviews Endocrinology, 2016Co-Authors: Giovanna Mantovani, Anna Spada, Francesca ElliAbstract:Differential diagnosis between Pseudohypoparathyroidism and related disorders of disrupted Gsα–cAMP signalling is a challenge for endocrinologists due to shared clinical and molecular characteristics. Here, Giovanna Mantovani and colleagues discuss both the current understanding and future challenges for the clinical and molecular diagnosis, classification and treatment of Pseudohypoparathyroidism and related disorders.
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genome wide dna methylation analysis of Pseudohypoparathyroidism patients with gnas imprinting defects
Clinical Epigenetics, 2016Co-Authors: Anne Rochtus, Francesca Elli, Giovanna Mantovani, Alejandro Martintrujillo, Benedetta Izzi, Intza Garin, Agnes Linglart, Guiomar Perez De Nanclares, Suzanne Thiele, Brigitte DecallonneAbstract:Background Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis.
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autosomal dominant Pseudohypoparathyroidism type ib a novel inherited deletion ablating stx16 causes loss of imprinting at the a b dmr
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesca Elli, Paolo Bordogna, Paolo Beckpeccoz, Anna Spada, Luisa De Sanctis, Erika Peverelli, Barbara Pivetta, Gianmaria Miolo, Giovanna MantovaniAbstract:Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant Pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods. Objective: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underl...
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Pseudohypoparathyroidism type ia and pseudo Pseudohypoparathyroidism the growing spectrum of gnas inactivating mutations
Human Mutation, 2013Co-Authors: Francesca Elli, Luisa Desanctis, Barbara Ceoloni, Anna Maria Barbieri, Paolo Bordogna, Paolo Beckpeccoz, Anna Spada, Giovanna MantovaniAbstract:: Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP-Ia), when maternally inherited, or pseudo-pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60-70% of affected subjects, most patients/families harbor private mutations and no genotype-phenotype correlation has been found to date. We investigated Gsα-coding GNAS exons in a large panel of PHP-Ia-PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, we identified 15 novel mutations in 19 patients. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS-locus-specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.
