GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs alpha

TY - JOUR

T1 - GNAS transcripts in skeletal progenitors

T2 - evidence for random asymmetric allelic expression of Gs alpha

AU - Michienzi, Stefano

AU - Cherman, Natasha

AU - Holmbeck, Kenn

AU - Funari, Alessia

AU - Collins, Michael T

AU - Bianco, Paolo

AU - Robey, Pamela Gehron

AU - Riminucci, Mara

PY - 2007/8/15

Y1 - 2007/8/15

N2 - Activating mutations of the Gsalpha 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 Gsalpha 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 Gsalpha 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 Gsalpha alleles are unequally expressed in both normal and FD-mutated stromal clones. However, in contrast to imprinting, the ratio of Gsalpha allelic expression is randomly established in different clones from the same patient. This result suggests that a parental-independent modulation of Gsalpha 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 Gsalpha, some of which may be relevant to the development of FD.

AB - Activating mutations of the Gsalpha 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 Gsalpha 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 Gsalpha 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 Gsalpha alleles are unequally expressed in both normal and FD-mutated stromal clones. However, in contrast to imprinting, the ratio of Gsalpha allelic expression is randomly established in different clones from the same patient. This result suggests that a parental-independent modulation of Gsalpha 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 Gsalpha, some of which may be relevant to the development of FD.

KW - Adolescent

KW - Adult

KW - Alleles

KW - Base Sequence

KW - Bone Marrow/metabolism

KW - Child

KW - Chromogranins

KW - Female

KW - Fibrous Dysplasia of Bone/genetics

KW - GTP-Binding Protein alpha Subunits, Gs/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Molecular Sequence Data

KW - Mutation

KW - Myoblasts, Skeletal/cytology

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Stromal Cells/cytology

U2 - 10.1093/hmg/ddm139

DO - 10.1093/hmg/ddm139

M3 - Journal article

C2 - 17566083

SN - 0964-6906

VL - 16

SP - 1921

EP - 1930

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -