Limits...
Progressive osseous heteroplasia: diagnosis, treatment, and prognosis.

Pignolo RJ, Ramaswamy G, Fong JT, Shore EM, Kaplan FS - Appl Clin Genet (2015)

Bottom Line: Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification.Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase.POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; The Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

ABSTRACT
Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS. The genetics, diagnostic criteria, supporting clinical features, current management, and prognosis of POH are reviewed here, and emerging therapeutic strategies are discussed.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of multiple transcripts from the GNAS locus.Notes: Gsα, XLαs, and NESP55 are the primary transcripts that produce proteins from the GNAS locus. GNAS-AS1 is transcribed in the antisense direction. All transcripts have distinct first exons that splice to common exons 2–13. Gsα is biallelic in most tissues. XLαs, A/B, and GNAS-AS1 are restricted to expression from the paternal allele, whereas NESP55 is only expressed maternally. Imprinting is regulated by differentially methylated regions (DMR) in the promoters. Alternative splicing leads to neuronal-specific transcripts Gsα-N1 and XLαs-N1, whereas a second open reading frame of XLαs leads to a protein called ALEX. Transcripts from maternal and paternal alleles are shown above and below, respectively. Bold lines indicate exons, and dashed lines indicate introns.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4321643&req=5

f1-tacg-8-037: Schematic diagram of multiple transcripts from the GNAS locus.Notes: Gsα, XLαs, and NESP55 are the primary transcripts that produce proteins from the GNAS locus. GNAS-AS1 is transcribed in the antisense direction. All transcripts have distinct first exons that splice to common exons 2–13. Gsα is biallelic in most tissues. XLαs, A/B, and GNAS-AS1 are restricted to expression from the paternal allele, whereas NESP55 is only expressed maternally. Imprinting is regulated by differentially methylated regions (DMR) in the promoters. Alternative splicing leads to neuronal-specific transcripts Gsα-N1 and XLαs-N1, whereas a second open reading frame of XLαs leads to a protein called ALEX. Transcripts from maternal and paternal alleles are shown above and below, respectively. Bold lines indicate exons, and dashed lines indicate introns.

Mentions: The GNAS gene is a highly complex locus that synthesizes several transcripts (Figure 1), the most abundant and best characterized of which encodes the ubiquitously expressed α-subunit of the stimulatory G protein (Gsα). Other protein-coding transcripts produce XLαs, the extra-large variant of Gsα (Gnasxl in mice), and NESP55, a neuroendocrine secretory protein (mouse Nesp).3,40,41 Each of the GNAS transcripts are initiated at unique promoters and first exons but share common downstream exons (exons 2–13 in humans and 2–12 in mice) of the GNAS locus (Figure 1). Alternative splicing of exon 3 generates short and long forms of both Gsα and XLαs, and neuronal-specific splicing to include exon N1, which resides between exons 3 and 4, leads to the Gsα-N1 and XLαs-N1 transcripts that have a truncated C terminus. A second open reading frame of XLαs mRNA produces a protein called ALEX that is unrelated to G-proteins. In addition, the transcripts A/B (mouse exon 1A) and GNAS antisense (human GNAS-AS1 or mouse Nespas) appear to be non-protein-coding transcripts, although translation of A/B is predicted to start at an in-frame ATG start site within exon 2 and to produce a truncated Gsα isoform.3,40–43


Progressive osseous heteroplasia: diagnosis, treatment, and prognosis.

Pignolo RJ, Ramaswamy G, Fong JT, Shore EM, Kaplan FS - Appl Clin Genet (2015)

Schematic diagram of multiple transcripts from the GNAS locus.Notes: Gsα, XLαs, and NESP55 are the primary transcripts that produce proteins from the GNAS locus. GNAS-AS1 is transcribed in the antisense direction. All transcripts have distinct first exons that splice to common exons 2–13. Gsα is biallelic in most tissues. XLαs, A/B, and GNAS-AS1 are restricted to expression from the paternal allele, whereas NESP55 is only expressed maternally. Imprinting is regulated by differentially methylated regions (DMR) in the promoters. Alternative splicing leads to neuronal-specific transcripts Gsα-N1 and XLαs-N1, whereas a second open reading frame of XLαs leads to a protein called ALEX. Transcripts from maternal and paternal alleles are shown above and below, respectively. Bold lines indicate exons, and dashed lines indicate introns.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321643&req=5

f1-tacg-8-037: Schematic diagram of multiple transcripts from the GNAS locus.Notes: Gsα, XLαs, and NESP55 are the primary transcripts that produce proteins from the GNAS locus. GNAS-AS1 is transcribed in the antisense direction. All transcripts have distinct first exons that splice to common exons 2–13. Gsα is biallelic in most tissues. XLαs, A/B, and GNAS-AS1 are restricted to expression from the paternal allele, whereas NESP55 is only expressed maternally. Imprinting is regulated by differentially methylated regions (DMR) in the promoters. Alternative splicing leads to neuronal-specific transcripts Gsα-N1 and XLαs-N1, whereas a second open reading frame of XLαs leads to a protein called ALEX. Transcripts from maternal and paternal alleles are shown above and below, respectively. Bold lines indicate exons, and dashed lines indicate introns.
Mentions: The GNAS gene is a highly complex locus that synthesizes several transcripts (Figure 1), the most abundant and best characterized of which encodes the ubiquitously expressed α-subunit of the stimulatory G protein (Gsα). Other protein-coding transcripts produce XLαs, the extra-large variant of Gsα (Gnasxl in mice), and NESP55, a neuroendocrine secretory protein (mouse Nesp).3,40,41 Each of the GNAS transcripts are initiated at unique promoters and first exons but share common downstream exons (exons 2–13 in humans and 2–12 in mice) of the GNAS locus (Figure 1). Alternative splicing of exon 3 generates short and long forms of both Gsα and XLαs, and neuronal-specific splicing to include exon N1, which resides between exons 3 and 4, leads to the Gsα-N1 and XLαs-N1 transcripts that have a truncated C terminus. A second open reading frame of XLαs mRNA produces a protein called ALEX that is unrelated to G-proteins. In addition, the transcripts A/B (mouse exon 1A) and GNAS antisense (human GNAS-AS1 or mouse Nespas) appear to be non-protein-coding transcripts, although translation of A/B is predicted to start at an in-frame ATG start site within exon 2 and to produce a truncated Gsα isoform.3,40–43

Bottom Line: Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification.Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase.POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; The Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

ABSTRACT
Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS. The genetics, diagnostic criteria, supporting clinical features, current management, and prognosis of POH are reviewed here, and emerging therapeutic strategies are discussed.

No MeSH data available.


Related in: MedlinePlus