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Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms.
- Source :
-
The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2015 Apr; Vol. 100 (4), pp. E681-7. Date of Electronic Publication: 2015 Jan 16. - Publication Year :
- 2015
-
Abstract
- Context: Pseudohypoparathyroidism type Ia (PHP1A) is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, multiple hormonal resistance, and features of Albright hereditary osteodystrophy. When the phenotype is present but not associated with hormonal resistance, it is called psedopseudohypoparathyroidism (PPHP). Both entities have been associated to GNAS haploinsufficiency, and are mostly caused by inherited inactivating mutations at GNAS gene that codes for the stimulatory alpha subunit of G protein, although the cause remains unidentified in approximately 30% of patients.<br />Objectives: The aims of our work were 1) to identify GNAS locus defects in 112 patients with clinical diagnosis of PHP1A/PPHP and no point mutations at GNAS, to improve molecular diagnostic and genetic counseling; 2) to outline the underlying molecular mechanism(s).<br />Methods: Methylation-specific-multiplex ligation-dependent probe amplification, qPCR, array comparative genomic hybridization, and long-PCR were used to search for genomic rearrangements at chromosome 20q and to identify their boundaries. We used different bioinformatic approaches to assess the involvement of the genomic architecture in the origin of the deletions.<br />Results: We discovered seven novel genomic deletions, ranging from 106-bp to 2.6-Mb. The characterization of five of seven deletion breakpoints and the definition of the putative molecular mechanisms responsible for these rearrangements revealed that Alu sequences play a major role in determining the genetic instability of the region.<br />Conclusion: We observed that deletions at GNAS locus represent a significant cause of PPHP/PHP1A and that such defects are mostly associated with Alu-mediated recombination events. Their investigation revealed to be fundamental as, in some cases, they could be misdiagnosed as imprinting defects.
- Subjects :
- Adolescent
Adult
Alu Elements genetics
Child
Child, Preschool
Chromogranins
Cohort Studies
Comparative Genomic Hybridization
Female
Genetic Loci
Humans
Infant
Male
Molecular Diagnostic Techniques
Young Adult
GTP-Binding Protein alpha Subunits, Gs genetics
Gene Deletion
Pseudohypoparathyroidism genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1945-7197
- Volume :
- 100
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of clinical endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 25594858
- Full Text :
- https://doi.org/10.1210/jc.2014-3098