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Osteopetrosis, literally 'stone bone', also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.
Osteogenesis imperfecta, colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth. Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (dissection) of the major arteries, such as the aorta; pulmonary valve insufficiency secondary to distortion of the ribcage; and basilar invagination.
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the TNFRSF11B gene.
An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and have an average half life of 25 years. They are derived from osteoprogenitor cells, some of which differentiate into active osteoblasts. Osteoblasts/osteocytes develop in mesenchyme.
Fraser syndrome is an autosomal recessive congenital disorder, identified by several developmental anomalies. Fraser syndrome is named for the geneticist George R. Fraser, who first described the syndrome in 1962.
Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium, transverse defects of the limbs, and mottling of the skin.
Sclerostin is a protein that in humans is encoded by the SOST gene. It is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues, and has anti-anabolic effects on bone formation.
Receptor activator of nuclear factor κ B (RANK), also known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANKL, and regulates the stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK.
Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.
Metaphyseal dysplasia, or Pyle disease, is a disorder of the bones. It is a rare disease in which the outer part of the shafts of long bones is thinner than normal and there is an increased chance of fractures. Its hallmark feature is an abnormality of the long bones in the arms and legs in which the ends (metaphyses) of the bones are abnormally broad; the shape of the bones resembles a boat oar or paddle. The broad metaphyses are due to enlargement of the spongy inner layer of bone. Although trabecular bone is expanded, the dense outermost layer of bone is thinner than normal. As a result, the bones are fragile and fracture easily. The bone abnormalities in the legs commonly cause knock knees in affected individuals.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.
Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.
Exostosin glycosyltransferase-2 is a protein that in humans is encoded by the EXT2 gene.
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Homeobox protein aristaless-like 4 is a protein that in humans is encoded by the ALX4 gene. Alx4 belongs to the group-1 aristaless-related genes, a majority of which are linked to the development of the craniofacial and/or appendicular skeleton, along with PRRX1, SHOX, ALX3, and CART1. The Alx4 protein acts as a transcriptional activator and is predominantly expressed in the mesenchyme of the developing embryonic limb buds. Transcripts of this gene are detectable in the lateral plate mesoderm just prior to limb induction. Alx4 expression plays a major role in the determination of spatial orientation of the growing limb bud by aiding in the establishment of anteroposterior polarity of the limb. It does this by working in conjunction with Gli3 and dHand to restrict the expression of Sonic Hedgehog (SHh) to the posterior mesenchyme, which will eventually give rise to the Zone of Polarizing Activity (ZPA). This gene has been proven to be allelic with mutations and deletions giving rise to a host of craniofacial dismorphologies and several forms of polydactyly in mammalian development. A mouse-model knockout of this gene, dubbed Strong's luxoid, was originally created by Forstheofel in the 1960s and has been extensively studied to understand the partial and complete loss-of-function properties of this gene.
Camurati–Engelmann disease (CED) is a very rare autosomal dominant genetic disorder that causes characteristic anomalies in the skeleton. It is also known as progressive diaphyseal dysplasia. It is a form of dysplasia. Patients typically have heavily thickened bones, especially along the shafts of the long bones. The skull bones may be thickened so that the passages through the skull that carry nerves and blood vessels become narrowed, possibly leading to sensory deficits, blindness, or deafness.
Van Buchem disease, or hyperostosis corticalis generalisata, is an autosomal recessive skeletal disease which is characterised by uninhibited bone growth, especially in the mandible, skull and ribs.
Franciscus Stephanus Petrus (Frans) van Buchem was a Dutch physician and professor, known for the discovery of Van Buchem disease, which was named after him. He married Elisabeth Euphemia Maria Christiana Nuijens in January, 1930, aged 32. His PhD thesis was supervised by Nobel prize winner Professor Willem Einthoven. Frans was, among other things, the Chief Physician in Internal Medicine of the St Elisabeth Hospital and after the end of World War Two, became a professor of Internal Medicine at the University of Groningen. In 1954, van Buchem diagnosed a patient with what he referred to as hyperosteosis corticales generalisata familiaris, later named Van Buchem disease. A year later, he published an article in Acta Radiologica on the disease.
References
- 1 2 3 4 5 Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Mar 2001). "Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)". Human Molecular Genetics. 10 (5): 537–43. doi: 10.1093/hmg/10.5.537 . PMID 11181578.
- ↑ Truswell AS (May 1958). "Osteopetrosis with syndactyly; a morphological variant of Albers-Schönberg's disease". The Journal of Bone and Joint Surgery. British Volume. 40-B (2): 209–18. PMID 13539104.
- ↑ Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (Feb 2002). "Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease". Journal of Medical Genetics. 39 (2): 91–7. doi:10.1136/jmg.39.2.91. PMC 1735035 . PMID 11836356.
- ↑ Sebastian A, Loots GG (March 2018). "Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models". Metabolism. 80: 38–47. doi: 10.1016/j.metabol.2017.10.005 . PMID 29080811.