Example Of Inborn Errors of Development Course Work

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Formation of bone during foetal development occurs through the process of ossification. This process is extremely important to proper bone length, density, and uniform skeletal formation. It is driven by a complex network of genes that code for signalling proteins whose function is to turn the ossification process on, off, or slow it down. Defects in these genes can cause problems with the ossification process, and can lead to conditions of skeletal dysplasia (improper formation of bone). One such condition is Achondroplasia, one of the most common forms of dwarfism, or congenital short stature (Lister Hill National Centre for Biomedical Communication 2014a).

Affecting 250,000 infants born each year worldwide (Ireland, Pacey, and Savariryan 2014: 117), the word Achondroplasia means “without cartilage formation” (Lister Hill National Centre for Biomedical Communication 2014a). However, the name may be misleading, as the disease is not an absence of cartilage, but an inability to convert cartilage into bone (Lister Hill National Centre for Biomedical Communication 2014a). Most commonly affected are the proximal limbs, such as the arms and legs; the head and trunk can sometimes remain disproportionately large (Ireland, Pacey, and Savarirayan 2014). These defects in skeletal formation have been linked to a gene that regulates ossification within the past two decades, and its mechanism is still not well understood, although the disease itself has been studied for many years (Horton 2005).

Achondroplasia was discovered more than 100 years ago, and, since the 1980’s, researchers have been trying to identify the gene responsible for the defect (Horton 2005: 166). Mouse models with the disorder were studied extensively, but were found to be too genetically different from humans to allow localization of the defective gene (Horton 2005). In 1994, two scientists, Francomano and Velini, identified the human FGFR3 gene through human genome mapping, finding the locus on chromosome 4 at position 480 on the DNA chain. It became known as a G480R mutation (Horton 2005: 166).

This G480 mutation was identified in most human Achondroplasia subjects at the time, and was identified as a missense mutation (Morrissey and Veinstein 2005: 154). This type of mutation involves substitution of one amino acid for another in the polypeptide chain of the DNA, often causing a completely different sequence that can alter the way a gene functions or its receptor protein regulates developmental processes (Russell 2006). In the case of this mutation, the normal amino acid glycine from the FGFR3 polypeptide is replaced with the amino acid arginine at position 480, which expresses itself in the growth plate of bone tissue (Horton 2005: 166). Since then, a second identical mutation at position 380 has also been identified as causative of Achondroplasia, called G380R (Lister Hill National Centre for Biomedical Communications 2014b). It is currently thought that these two mutations are responsible for 99% of cases worldwide; although it is also theorized that there may be other unidentified mutations causing an additional 1% of cases (Lister Hill National Centre for Biomedical Communications 2014b).

Mapping the human genome was used to initially identify the gene with the mutation, as animal models were not successful (Horton 2005: 166). However, mice were subsequently used to study the mechanism by which the genetic defect caused Achondroplasia (Horton 2005: 166). While not every aspect of this mechanism has been discovered, and there are still several mysteries surrounding its ability to disrupt normal bone formation, the basic mechanism is now fairly well understood (Ornitz 2005).

Knockout experiments performed on mice revealed that the FGRFP3 gene codes for a protein called FGFR3 protein (Horton 2005: 167). While there are several different types (isoforms) of the FGFR3 protein produced from the FGFR3 gene, the majority of these exist in bone tissue, at or near the site of the growth plate (Lister Hill National Centre for Biomedical Communication 2014b). They are responsible for limiting the production of bone from cartilage (ossification) during the earliest stages of development (Ornitz 2005).
During the first stage of normal bone development, a process called mesenchymal condensation occurs, stimulated by FGFR1 and FGFR2 genes (Ornitz 2005: 208). These genes signal mesenchymal (stem) cells to accumulate (Ornitz 2005: 208). Once accumulated, the next stage is chondrogenesis, or the development of cartilage (Ornitz 2005: 209). The mesenchymal cells differentiate into cartilage cells, forming plenty of cartilage for the next stage of bone development. After chondrogenesis is complete, newly formed cartilage begins to turn to bone in a process called ossification, a process that is “turned on” by several other Fibroblast Growth Factor genes and their receptor proteins (Ornitz 2005). During ossification, FGFR3 is expressed. FGFR3 acts as the “off” switch for the process of ossification: it sends the proper signals to slow or stop the ossification process once enough bone has been developed (Ornitz 2005: 211). This prevents excessive amounts of bone from being formed. The FGFR3 gene accomplishes this by instructing the body to produce an FGFR3 protein, a Fibroblast Growth Factor Receptor protein, which is responsible for binding to signalling molecules and sending the “stop” signal to the cells Howard 2005: 167).
The Fibroblast Growth Factor Receptor 3 (FGFR3) protein is located across the cell membrane, with part of the protein outside and part of the protein inside the cell, to allow communication to be transmitted from outside genetic factors to the interior of the cell (Lister Hill National Centre for Biomedical Communication 2014b). Once it has received a particular signal from outside the cell, the protein becomes activated, transmits the signal into the cell, and instructs the cell to limit ossification (Ornitz 2005: 211).

In the case of the genetic defect that causes Achondroplasia, the missense mutation in the gene causes a sequence of unusual events to occur. First, the gene produces an abnormal FGFR3 monomer (a molecule with the capability to bind to certain other molecules) as its product; the product of the gene binds to the FGFR3 protein, as it ordinarily would, but because the monomer structure is abnormal, it activates an excess of the substance tyrosine kinase on the surface of the receptor protein (Horton 2005: 166). Tyrosine kinase is a cell surface receptor that has a strong binding capability.

When the receptor protein undergoes phosphorylation (a normal process in gene/protein receptor signalling), the excess tyrosine kinase causes the receptor to change shape completely, gaining additional sites for molecular attachment (Horton 2005: 167). Now, instead of having only one or two sites for the attachment of signalling molecules (those that ultimately stimulate the signals that are sent to the bone tissue), it has many sites for signal molecules to attach (Horton 2005: 167). This attracts a larger number of signalling molecules than usual, and a large number of signals are sent, telling the ossification process to stop (Horton 2005: 167). This results in premature truncation of ossification, particularly in the proximal limbs, as this appears to be primarily where the FGFR3 gene is most active (Ornitz 2005). Much of this is still theory, as many researchers are still unclear as to how, at the molecular level, this genetic defect limits bone growth. However, two things are well proven through scientific research: the FGFR3 gene is responsible for encoding a protein that limits ossification, so in some way, too many ossification limiting signals are being sent (Howard 2005); and the outward features and complications seen in individuals with this defect can be directly attributed to inadequate bone and cartilage formation (Ireland, Pacey, and Savarirayan 2014).

The most common, and most visible, consequence of inadequate bone formation in Achondroplasia is dwarfism, or short stature (Russell 2006). The average height for males with this disorder is 131 centimetres, and for females, 124 centimetres (Lister Hill National Centre for Biomedical Communication 2014a). In addition to their short stature, the appearance of a child or adult with the disorder is unique, with several typical features: broad hands with a trident appearance, narrow trunk, broad forehead and skull, thin flat face, and macrocephaly (the condition of an enlarged skull and brain) (Lister Hill National Centre for Biomedical Communication 2014a). Aside from characteristic, outwardly visible physical features, however, these individuals often present with a number of developmental and medical conditions related to improper development of bone that are not as well known, or outwardly visible (Ireland, Pacey, and Savarirayan 2014).

It has been well documented that “disproportionate growth between endochondral bone and the underlying organs leads to a number of orthopaedic, neurological, respiratory, ear, nose, and throat (ENT), and dental issues” (Ireland, Pacey, and Savarirayan 2014: 118) for individuals with this disorder.
Macrocephaly, the condition of an enlarged head, is one of the most common orthopaedic complications of the disorder. The exact reason for this is still currently limited to speculation, but it is thought that perhaps it is because the FGFR3 gene is less active in the bones of the skull (Ornitz, 2005). Other researchers believe it may be due to the associated conditions of communicating hydrocephalus (water in the brain) or dilated ventricles (enlarged portions) of the brain, leading to an enlarged skull (Ireland, Pacey, and Savarirayan 2014: 120). These defects could be caused by a few faulty FGFR3 receptors that reside in the neurological tissue, affecting neurological development in a similar manner to bone development (Morrissy and Veinstein 2006). Unfortunately, macrocephaly is not the only orthopaedic complication.

Because proximal limbs are shortened, but trunk size may remain the same, persons with this disease may have difficulty reaching areas of their body others would not, such as the head or feet (Lister Hill National Centre for Biomedical Communication 2014a). Additionally, due to abnormal cartilage formation, these individuals often present with joint hypermobility. Hypermobile joints are more flexible than most, with the tendency to bend backward a certain degree (Ireland, Pacey, and Savarirayan 2014: 121). Collagen (cartilage) is typically needed in exact amounts to allow for the right amount of joint flexion – not too much, not too little. Because the FGFR3 gene is over abundantly limiting the conversion of cartilage to bone during development, an excess of cartilage may be present within the joints, allowing a greater than normal degree of flexion (Ireland, Pacey, and Savarirayan 2014: 121). This pre-disposes the individual to fractures, dislocations, sprains, and other injuries, even through normal daily activities Ireland, Pacey, and Savarirayan 2014: 121). Other similar conditions, such as those that affect bone density, can also occur and cause predisposition to injury, such as diminished bone density and loss of bone strength.
A complete ossification process is necessary for bone strength and density; limitations in these areas will occur if ossification is prematurely stopped. In Achondroplasia, certain bones, in particular those of the leg (such as the tibia) can begin to bend, or bow, by the time the patient has reached late childhood or early adulthood (Ireland, Pacey, and Savarirayan 2014: 122). This deformity can limit the ability to walk, as well as cause chronic pain, and predispose the patient to fractures or other injuries (Ireland, Pacey, and Savarirayan 2014: 121). Similarly, the spinal column – including the skeletal bone – may also be affected, causing pain and limiting mobility.

Over 90% of infants with this disorder also present with abnormalities of the spinal column, as it is also affected by abnormal ossification (Ireland, Pacey, and Savarirayan 2014: 121). Kyphosis, an abnormal curvature of the spine causing a hunched back, is common (Lister Hill National Centre for Biomedical Communication 2014a). Responsible for movement difficulties and pain, and in some cases requiring surgery, it often resolves on its own once the child is old enough to walk (Ireland, Pacey, and Savarirayan 2014: 121).
Neurological complications are also abundant, due to disproportionate development of the foramen magnum – the hole in the skull through which the spinal cord, nerves, and blood vessels pass – and other structures, such as the spine and spinal cord (Ireland, Pacey, and Savarirayan 2014: 125). The foramen magnum is typically too small in relation to these other structures, causing compression of the spinal cord (Ireland, Pacey, and Savarirayan 2014: 125). This compression can lead to a number of abnormalities, including respiratory depression, small underdeveloped airways, and sleep apnoea (Ireland, Pacey, and Savarirayan 2014: 125). Other abnormalities of skull development may also be present, leading to alterations in sensory development.

Because hearing acuity also requires intact bone structure to conduct sound through the ear canal, in a process called conductive hearing, lack of, or inappropriate, bone formation in this area can cause a number of problems. Among them, hearing difficulty and deafness are some of the most common (Ireland, Pacey, and Savarirayan 2014: 129). Unfortunately, abnormally shaped ear canals due to incomplete ossification of bony structures in the ear can also cause inadequate drainage, and lead to frequent ear infections (Ireland, Pacey, and Savarirayan 2014: 125).

Achondroplasia, the most common form of skeletal dysplasia and dwarfism, appears to be a unique and complex disease, with a genetic basis that has yet to be fully understood despite years of study. The clinical presentation includes many classic, common physical features of dwarfism (such as short stature) but also includes many other defects of the skeletal and other organ systems that have ultimately all been linked to an incomplete ossification process during foetal development. Many years of study have led to a thorough understanding of the clinical complications, but only within the last two decades has the genetic basis become apparent. Definitively linked to one gene mutation that causes the bone building process to stop prematurely, the exact mechanism is still currently theory. This defect is an excellent example of the complicated but minute genetic defects that can have far-reaching effects on development and function, and the time and effort it takes to uncover their complex mechanisms.

List of References

Horton, W. (2005) ‘Recent Milestones in Achondroplasia Research’. American Journal of Medical Genetics [online] 140A, 166-169 available from
Ireland, P., Pacey, V., & Savariryan, R. (2014) ‘Optimal management of complications associated with Achondroplasia’. The Application of Clinical Genetics [online] 7, 117-125 available from
< http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104450/> [21 Nov 2014]
Lister Hill National Centre for Biomedical Communications (2014a) Achondroplasia [online] available from [20 November 2014]
Lister Hill National Centre for Biomedical Communications (2014b) FGFR3 [online] available from [20 November 2014]
Morrissy, R., and Veinstein, S. (2006) Paediatric Orthopaedics. Philadelphia: Lippincott Williams & Wilkins.
Ornitz, D. (2005) ‘FGF Signalling Pathways in the Development of the Endochondral Skeleton’ Cytokine & Growth Factor Reviews [online] 16(2), 205-213 available from [22 November 2014]
Russell, P. (2006) iGenetics: A Mendelian Approach. San Francisco: Pearson Education.

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