Significant difference of opinion regarding the role of noggin in fibrodysplasia ossificans progressiva

Warman, Matthew L.

doi:10.1002/ajmg.10290

Cited by 6 publications

(5 citation statements)

References 4 publications

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“…Previous studies have proposed that BMP2/4 or their antagonist noggin is responsible for the symptoms of FOP. However, dysfunction of BMPs and noggin in individuals with FOP remains to be elucidated (Cohen, 2002;Warman, 2002;Xu et al, 2000). The involvement of BMPs in ectopic bone formation in skeletal muscle has not been shown in human disorders.…”

Section: Discussionmentioning

confidence: 94%

Osteogenic properties of human myogenic progenitor cells

Hashimoto

Kiyono²,

Wada

et al. 2008

Mechanisms of Development

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Here, we identified human myogenic progenitor cells coexpressing Pax7, a marker of muscle satellite cells and bone-specific alkaline phosphatase, a marker of osteoblasts, in regenerating muscle. To determine whether human myogenic progenitor cells are able to act as osteoprogenitor cells, we cultured both primary and immortalized progenitor cells derived from the healthy muscle of a nondystrophic woman. The undifferentiated myogenic progenitors spontaneously expressed two osteoblast-specific proteins, bone-specific alkaline phosphatase and Runx2, and were able to undergo terminal osteogenic differentiation without exposure to an exogenous inductive agent such as bone morphogenetic proteins. They also expressed the muscle lineage-specific proteins Pax7 and MyoD, and lost their osteogenic characteristics in association with terminal muscle differentiation. Both myoblastic and osteoblastic properties are thus simultaneously expressed in the human myogenic cell lineage prior to commitment to muscle differentiation. In addition, C3 transferase, a specific inhibitor of Rho GTPase, blocked myogenic but not osteogenic differentiation of human myogenic progenitor cells. These data suggest that human myogenic progenitor cells retain the capacity to act as osteoprogenitor cells that form ectopic bone spontaneously, and that Rho signaling is involved in a critical switch between myogenesis and osteogenesis in the human myogenic cell lineage.

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Section: Discussionmentioning

confidence: 94%

Osteogenic properties of human myogenic progenitor cells

Hashimoto

Kiyono²,

Wada

et al. 2008

Mechanisms of Development

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show abstract

“…Characteristic anomalies of the cervical spine include large posterior elements, tall narrow vertebral bodies, and fusion of the facet joints between C2 and C7, findings that are strikingly similar to those seen in mice with homozygous deletions of the gene encoding Noggin, a secreted bone morphogenetic protein (BMP) antagonist [26], supporting that increased BMP pathway signaling underlies the disease [25]. Although mutations in the Noggin gene have been reported [27–29], these findings could not be reconfirmed and are thought to be in error [30–34]. …”

Section: Additional Skeletal Anomalies In Fopmentioning

confidence: 99%

Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)

et al. 2008

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Metamorphosis, the transformation of one normal tissue or organ system into another, is a biological process rarely studied in higher vertebrates or mammals, but exemplified pathologically by the extremely disabling autosomal dominant disorder fibrodysplasia ossificans progressiva (FOP). The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein type I receptor that causes skeletal metamorphosis in all classically affected individuals worldwide, is the first identified human metamorphogene. Physiological studies of this metamorphogene are beginning to provide deep insight into a highly conserved signaling pathway that regulates tissue stability following morphogenesis, and that when damaged at a highly specific locus (c.617G > A; R206H), and triggered by an inflammatory stimulus permits the renegade metamorphosis of normal functioning connective tissue into a highly ramified skeleton of heterotopic bone. A comprehensive understanding of the process of skeletal metamorphosis, as revealed by the rare condition FOP, will lead to the development of more effective treatments for FOP and, possibly, for more common disorders of skeletal metamorphosis.

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“…In addition, three novel mutations in NOG published by Semonin et al were subsequently challenged to be technical PCR errors due to the use of a nested PCR approach [28], [36]. Consequently, the necessity to present photographs and radiographs of the studied FOP patients has been emphasized to assure the correct clinical diagnosis and that the same phenotypes are compared [34]. Upon identification of heterozygous missense activating mutations in ACRV1 as the genetic cause of FOP in 2006, additional questions regarding the validity of NOG mutations in FOP were raised [15], [27], [30], [33], [37].…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Alleged NOGGIN Mutation G92E Disproves Its Pathogenic Relevance

et al. 2012

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We identified an amino acid change (p.G92E) in the Bone Morphogenetic Protein antagonist NOGGIN in a 22-month-old boy who presented with a unilateral brachydactyly type B phenotype. Brachydactyly type B is a skeletal malformation that has been associated with increased Bone Morphogenetic Protein pathway activation in other patients. Previously, the amino acid change p.G92E in NOGGIN was described as causing fibrodysplasia ossificans progressiva, a rare genetic disorder characterized by limb malformations and progressive heterotopic bone formation in soft tissues that, like Brachydactyly type B, is caused by increased activation of Bone Morphogenetic Protein signaling. To determine whether G92E-NOGGIN shows impaired antagonism that could lead to increased Bone Morphogenetic Protein signaling, we performed functional assays to evaluate inhibition of BMP signaling. Interestingly, wt-NOGGIN shows different inhibition efficacies towards various Bone Morphogenetic Proteins that are known to be essential in limb development. However, comparing the biological activity of G92E-NOGGIN with wt-NOGGIN, we observed that G92E-NOGGIN inhibits activation of bone morphogenetic protein signaling with equal efficiency as wt-NOGGIN, supporting that G92E-NOGGIN does not cause pathological effects. Genetic testing of the child's parents revealed the same amino acid change in the healthy father, further supporting that p.G92E is a neutral amino acid substitution in NOGGIN. We conclude that p.G92E represents a rare polymorphism of the NOGGIN gene - causing neither brachydactyly nor fibrodysplasia ossificans progressiva. This study highlights that a given genetic variation should not be considered pathogenic unless supported by functional analyses.

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Significant difference of opinion regarding the role of noggin in fibrodysplasia ossificans progressiva

Cited by 6 publications

References 4 publications

Osteogenic properties of human myogenic progenitor cells

Osteogenic properties of human myogenic progenitor cells

Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)

Functional Analysis of Alleged NOGGIN Mutation G92E Disproves Its Pathogenic Relevance

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