Molecular Definition of Pseudohypoparathyroidism Variants
Autor: | Harald Jüppner |
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Rok vydání: | 2021 |
Předmět: |
musculoskeletal diseases
0301 basic medicine medicine.medical_specialty Gs-alpha Endocrinology Diabetes and Metabolism Clinical Biochemistry 030209 endocrinology & metabolism Biology Biochemistry Epigenesis Genetic Loss of heterozygosity GNAS 03 medical and health sciences 0302 clinical medicine Endocrinology cAMP Internal medicine Chromogranins GTP-Binding Protein alpha Subunits Gs medicine GNAS complex locus Humans Epigenetics Pseudohypoparathyroidism phosphate Genetics Mini-Reviews calcium epigenetics TSH Biochemistry (medical) pseudohypoparathyroidism DNA Methylation medicine.disease parent-specific GNAS methylation 030104 developmental biology Differentially methylated regions Molecular Diagnostic Techniques Uniparental Isodisomy STX16 biology.protein Pseudopseudohypoparathyroidism AcademicSubjects/MED00250 PTH |
Zdroj: | The Journal of Clinical Endocrinology and Metabolism |
ISSN: | 1945-7197 0021-972X |
Popis: | Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright’s hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q). |
Databáze: | OpenAIRE |
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