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Abstract
BackgroundPseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases, with no known underlying primary genetic lesions, could represent true stochastic errors in early embryonic maintenance of methylation. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs.ResultsWith respect to mosaic conditions, the study of multiple tissues is a necessary approach; thus, we investigated somatic cell lines (peripheral blood and buccal epithelium and cells from the urine sediment) descending from different germ layers from 19 PHP patients (11 spor-PHP1B, 4 GNAS mutated PHP1A, and 4 PHP with no GNAS (epi)genetic defects) and 5 healthy controls. We identified 11 patients with epigenetic defects, further subdivided in groups with complete or partial methylation defects. The recurrence of specific patterns of partial methylation defects limited to specific CpGs was confirmed by checking methylation profiles of spor-PHP1B patients diagnosed in our lab (n = 56). Underlying primary genetic defects, such as uniparental disomy or deletion, potentially causative for the detected partial methylation were excluded in all samples.ConclusionsOur data showed no differences of methylation levels between organs and tissues from the same patient, so we concluded that the epimutation occurred in early post-zygotic phases and that the partial defects were mosaics. The number of patients with no detectable (epi)genetic GNAS defects was too small to exclude epimutations occurring in later post-zygotic phases, affecting only selected tissues different from blood, thus leading to underdiagnosis during routine molecular diagnosis. Finally, we found no correlation between methylation ratios, representing the proportion of epimutated cells, and the clinical presentation, further confirming the hypothesis of a threshold effect of the GNAS loss of imprinting leading to an “all-or-none” phenotype.
Highlights
Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities
In 2000, the PHP1B phenotype was associated with a loss of imprinting (LOI), at one or more GNAS differentially methylated regions (DMRs), which disrupts the parental-specific expression of its transcripts
We investigated genomic DNA samples obtained from different tissues of 5 healthy controls, 1 patient with PHP1A due to a large GNAS deletion, considered as a positive reference for methylation studies, and 19 PHP patients (11 spor-PHP1B, 4 GNAS-mutated PHP1A, and 4 PHP with no GNASgenetic defects)
Summary
Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs. Pseudohypoparathyroidism type 1B (PHP1B; MIM # 603233) is a rare imprinting disorder (ID) characterized by renal resistance to parathyroid hormone (PTH) in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases (spor-PHP1B) present a broad GNAS LOI with no known underlying genetic lesion; they could represent true stochastic errors in early embryonic maintenance of methylation [10]. The DNA methylation undergoes a process of erasure, acquisition, and maintenance during gametogenesis, it is maintained during the epigenetic reprogramming in the pre-implantation embryo, and disruptions in any of these steps may lead to IDs, resulting in the aberrant development of embryogenesis, placentation, and postnatal growth [13,14,15]
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