Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3
| Autor: | Maria Antonia Maffini, L. deSanctis, Arianna Pirelli, Agnès Linglart, Maura Arosio, Giovanna Mantovani, Francesca Elli, Paolo Bordogna, Daniele Tessaris |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Candidate gene 2q37 Drug Resistance lcsh:Medicine Thyrotropin Gs 0302 clinical medicine GTP-Binding Protein alpha Subunits Gs Genetics (clinical) Genetics biology Imprinting GTP-Binding Protein alpha Subunits Phenotype 030220 oncology & carcinogenesis Chromosomes Human Pair 2 Pseudohypoparathyroidism Pair 2 Female Chromosome Deletion Human musculoskeletal diseases lcsh:QH426-470 iPPSD Chromosomes AHO GNAS Methylation defect Modifier gene PHP-1B Chromogranins Genetic Association Studies Genetic Heterogeneity Genomic Imprinting Humans 03 medical and health sciences medicine GNAS complex locus Epigenetics Molecular Biology Genetic heterogeneity Research lcsh:R Brachydactyly medicine.disease Human genetics lcsh:Genetics 030104 developmental biology biology.protein Genomic imprinting Developmental Biology |
| Zdroj: | Clinical Epigenetics Clinical Epigenetics, Vol 11, Iss 1, Pp 1-8 (2019) |
| ISSN: | 1868-7083 1868-7075 |
| Popis: | Background The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. Results The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. Conclusions For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B. Electronic supplementary material The online version of this article (10.1186/s13148-018-0607-8) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink