[Epigenetics and pseudohypoparathyroidism].
Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). This imprint is tissue-specific, mainly localized in the kidney and the thyroid. Only the maternal allele is expressed at this level. An alteration in the coding sequence of the gene leads to an haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as a PHP1a. If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudo-pseudo-hypoparathyroidism (PPHP). Methylation anomalies of GNAS locus, in particular of exon 1A, are responsible for a lack of expression of Gαs at kidney and thyroid levels only. If these anomalies concern the maternal allele (the only one expressed) with a paternal pattern, there is no haplo-insufficiency and no dysmorphic syndrome. The hormonal resistance is yet again limited to PTH and TSH. The phenotype is known as PHP1b. In the familial forms, these methylation anomalies are associated with a deletion of the syntaxine 16 gene in the maternal allele. This gene contains probably the imprinting center of the locus.
Richard
N
N
Laboratoire de Génétique Moléculaire, Département Génétique et Reproduction, CHU de Caen, avenue G.-Clemenceau, 14033 Caen, France.
Abéguilé
G
G
Coudray
N
N
Kottler
M-L
ML
D000818:Animals; D002864:Chromogranins; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005799:Genes, Dominant; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010281:Parathyroid Hormone / Q000502:physiology; D010641:Phenotype; D011547:Pseudohypoparathyroidism / Q000235:genetics*; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics; D051438:Syntaxin 16 / Q000235:genetics / Q000502:physiology; D013961:Thyroid Gland / Q000378:metabolism; D013972:Thyrotropin / Q000502:physiology
D002864:Chromogranins; D010281:Parathyroid Hormone; C496118:STX16 protein, human; D051438:Syntaxin 16; D013972:Thyrotropin; C406732:GNAS protein, human; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs