Human Molecular Genetics Advance Access originally published online on June 12, 2007
Human Molecular Genetics 2007 16(16):1921-1930; doi:10.1093/hmg/ddm139
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs
1 Fondazione Parco Scientifico San Raffaele, 00128 Roma, Italy, 2 Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, MD 20892, USA, 3 Dipartimento di Medicina Sperimentale, Università dell’Aquila, 67100 L’Aquila, Italy and 4 Dipartimento di Medicina Sperimentale, Università La Sapienza, 00161 Roma, Italy
* To whom correspondence should be addressed at: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, 30 Convent Drive MSC 4320, Building 30, Room 228, Bethesda, MD 20892, USA. Tel: +1 3014964563; Fax: +1 3014020824; Email: probey{at}dir.nidcr.nih.gov
Received March 23, 2007; Revised May 9, 2007; Accepted May 13, 2007
Activating mutations of the Gs
gene, encoded by the guanine nucleotide-binding protein, alpha stimulating (GNAS) locus located on chromosome 20q13, underlie different clinical phenotypes characterized by skeletal lesions [fibrous dysplasia (FD) of bone], extraskeletal diseases (mainly endocrine hyperfunction and skin hyperpigmentation) and variable combinations thereof [the McCune–Albright syndrome (MAS)]. This clinical heterogeneity is commonly assumed to reflect the post-zygotic origin of the mutation. However, the pattern of imprinting of the Gs gene in some human post-natal tissues suggests that parental-dependent epigenetic mechanisms may also play a role in the phenotypic effect of the mutated GNAS genotype. FD lesions are generated by mutated clonogenic osteoprogenitors that reside, along with their normal counterparts, in FD bone marrow stroma. We analyzed the allelic expression pattern of Gs and other GNAS alternative transcripts in the progeny of normal and mutated clonogenic stromal cells isolated in vitro from a series of informative FD/MAS patients. We report here for the first time that the two Gs alleles are unequally expressed in both normal and FD-mutated stromal clones. However, in contrast to imprinting, the ratio of Gs allelic expression is randomly established in different clones from the same patient. This result suggests that a parental-independent modulation of Gs expression occurs in clonogenic osteoprogenitor cells and, at the single cell level, may impact on the severity of an FD lesion. Furthermore, we show that normal and mutated clonogenic stromal cells express GNAS alternative transcripts other than the common Gs, some of which may be relevant to the development of FD.
The authors wish it to be known that, in their opinion, these two authors should be regarded as joint senior authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Aydin, N. Aytan, M. J. Mahon, H. A. W. Tawfeek, N. W. Kowall, A. Dedeoglu, and M. Bastepe Extralarge XL{alpha}s (XXL{alpha}s), a Variant of Stimulatory G Protein {alpha}-Subunit (Gs{alpha}), Is a Distinct, Membrane-Anchored GNAS Product that Can Mimic Gs{alpha} Endocrinology, August 1, 2009; 150(8): 3567 - 3575. [Abstract] [Full Text] [PDF]
|
|