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Activities like walking, running, dancing, cycling, and many more require a healthy patella, while the main function of a fingernail is to protect the fingertip and its surrounding tissues from injuries. A developmental disorder that produces abnormalities in both of these body parts is Nail-Patella Syndrome (NPS). Nail deformities are viewed in almost all individuals with NPS, and the nails can be completely absent or underdeveloped. Typically, the fingernails are altered more than the toenails, and the thumbnails display the most serious effects (Witzgall, 2017). Additionally, NPS leads to abnormalities in people’s knees, elbows, hips, eyes, and kidneys. As a result, the patellae are small, improperly shaped, or completely absent, while the elbows can be angled outward. Iliac horns develop from horn-like projections of the iliac bones of the pelvis, which is usually only seen in people with this disorder. NPS also increases an individual’s risk of developing glaucoma and kidney failure. People can be severely impacted by one facet of this disorder, while not being affected elsewhere; it varies from person-to-person. NPS is quite rare since the incidence has been established at around 1 in every 50,000 newborns (Sweeney et al., 2003).
NPS is an autosomal dominant condition, which means that the abnormal gene is only needed from one parent to exhibit the disorder. This abnormal gene occurs through mutations in the LMX1B gene. This illustrates the reason for the skeletal deformities in these individuals because LMX1B regulates the dorsal-ventral limb patterning (Witzgall, 2017). This disorder is also classified as a pleiotropic birth defect since it affects multiple unrelated phenotypic traits. NPS was shown to be genetically linked with the ABO blood type, and this was one of the first disorders where a genetic linkage was determined. However, no association between the severity of the phenotypes has been determined between parent and child (Sweeney et al., 2003). Before specifically analyzing how development is affected in NPS, it will help to first explain the normal development of the patella, so that this can then be compared to the abnormal development found in NPS.
Normal Patella Development
The patella, also known as the kneecap, is classified as a sesamoid bone since it is enclosed within the quadriceps and patellar tendons. The essential functional role of the patella is knee extension since it increases the weight that the quadriceps tendon can expend on the femur by raising the angle of action (Márquez-Flórez et al., 2018). The rudimentary form of the human patella is first seen at seven weeks of development, while it starts to convert into cartilage by the eighth week. The actual formation of the bone does not start until around 14 weeks after birth, but it is not completely visible until 4 years of age. The patella exhibits a thick, circular-triangular shape, while protecting the anterior surface of the knee joint (Eyal et al., 2015).
The process of developing the patella begins with generating the dorsal axis. The Wnt7a gene is expressed within the dorsal, but not ventral, ectoderm of the limb buds. Once Wnt7a becomes expressed, then this leads to the activation of the LMX1B gene in the dorsal mesenchyme. LMX1B produces a transcription factor that is critical for determining the dorsal positioning of cells within the limb. If the LMX1B protein were to be induced in ventral mesenchyme cells, then even these cells would still establish a dorsal phenotype, which illustrates the impact that LMX1B has on dorsal positioning (Gilbert and Barresi, 2016). Once the dorsal positioning has been determined, then the patella can initially start to develop as a subset of the femur. This involves the presence of Sox9 and Scx positive progenitor cells. This has been validated since it has been shown that Sox9 and Scx were expressed in both femur and patella cell populations, which means that the patella progenitor cells originate from the femur (Eyal et al., 2015). Also, Sox9 and Scx lead to the initiation of patella development as part of the femur before the complete development of the quadriceps tendon (Márquez-Flórez et al., 2018).
The Sox9 and Scx positive progenitors rely on both TGF and BMP4 signaling for differentiation and specification of their cells. TGF specifies Sox9 and Scx cells for patella formation since no patella cells formed when TGF signaling was knocked out from early limb mesenchyme; Sox9 and Scx expression was lost in all of the patella progenitors. BMP4 is then needed for the differentiation of the patella progenitor cells, so that these can then form into the various necessary parts of the patella. The cells with Scx and BMP can now begin to differentiate into chondrocytes, which are early cartilage cells (Eyal et al., 2015). From the surrounding muscle, the presence of Scx cells is perceived, and this results in the muscle cells releasing Fibroblast Growth Factor (FGF). FGF, which diffuses from the muscle into the Scx cells, leads to the differentiation of early tendon cells, known as tenocytes. At this point, the patella must separate from the femur, which occurs through joint formation (Márquez-Flórez et al., 2018). In joint formation, interzone cells are the cells that become specified as joint progenitors. These interzone cells start to express Wnt9a and Wnt4, and this allows the formation of joint cells instead of cartilage. The joint cells generate a long, flat shape, which allows the patella to separate from the femur at this junction. Again, Sox9 plays an important role in this process since it is expressed in the patella cells, but not in the interzone cells (Eyal et al., 2015). Muscle contraction also helps with forming the joint cells and separating the patella from the femur. In the absence of muscle contraction, the interzone cells are unable to become joint cells and remain as chondrocytes, thus preventing joint formation and keeping the patella and femur together. Although muscle contraction does not impact the inception of the patella, it is critical during the separation from the femur (Márquez-Flórez et al., 2018).
The development of NPS is primarily caused by loss of function mutations in the LMX1B gene. This gene is found on human chromosome 9q34, and it consists of eight exons, which encode around 372 amino acids. The LMX1B protein is composed of two zinc-binding LIM domains at its amino-terminus, along with a DNA-binding homeodomain, which is where the protein binds to specific regions of the target genes (Marini et al., 2010). The LIM1 domain is encoded by exon 2, LIM2 by exon 3, and the homeodomain by exons 4 through 6 (Witzgall, 2017). Northern blot analysis has revealed large amounts of LMX1B expression in fetal skeletal muscles, kidneys, and testis (Vollrath et al., 1998). NPS is inherited in an autosomal dominant fashion. When a person with an abnormality in the LMX1B gene has children, there is a 50% chance for each child to inherit the abnormal copy of the gene and develop NPS (Sweeney et al., 2003). The different LMX1B mutations were first discovered by screening numerous families who exhibited common symptoms of NPS, like absent patellae and fingernails. Within these families, genomic DNA was drawn from whole blood. Mutations were analyzed utilizing mutation-detection enhancement and DNA sequencing (McIntosh et al., 1998). From the first four families, four mutations were identified: two nonsense mutations, one frameshift mutation, and one missense mutation. The appearance of earlier than expected stop codons led to a reduction in the amino acid sequence compared to the normal sequence. These nonsense mutations shortened the LIM1 domain and homeodomain, and these are important components of the LMX1B protein. The missense mutation resulted in the conversion of cysteine to phenylalanine within the amino acid sequence. By replacing cysteine with phenylalanine, this prevents the formation of the LIM2 domain (Vollrath et al., 1998).
Furthermore, within the rest of the families that were screened, a total of 25 mutations were identified, which again included nonsense, frameshift, and missense mutations. The nonsense mutations produced a shortened protein product, along with instability of the mutant mRNA. This caused the LMX1B protein product to be nonfunctional due to the loss of the LMX1B protein sequence beyond the mutation. The frameshift mutations resulted in the loss of at least one exon within the protein, thus severely reducing its size and stability (McIntosh et al., 1998). The overwhelming majority of mutations have been found in exons 2 through 6, which affects the roles of the LIM domains and the homeodomain (Vollrath et al., 1998). In the case of the LIM domains, the missense mutations lead to the replacement of the amino acids that are critical for the binding of zinc at the amine-terminus. For the homeodomain, the substitution of amino acids prevented the binding of LMX1B to DNA (Witzgall, 2017). Also, deletions of the entire LMX1B gene have recently been reported as well. Although all of these different mutations have been determined, a correlation has not been discovered yet between the site of the mutation and the severity of the NPS symptoms. These mutations all yield a combination of the same common symptoms (Marini et al., 2010).
These mutations within the LMX1B gene definitely explain the abnormalities of the patellae found in NPS patients. Since the mutations result in a nonfunctional LMX1B protein product, then this means that this transcription factor cannot determine the dorsal positioning of cells within the limb from the dorsal mesenchyme. A non-mutated and functional LMX1B protein is needed to properly be able to determine the dorsal positioning (Gilbert and Barresi, 2016). The importance of LMX1B in development was shown in knockout mice that were generated without the LMX1B gene. As a result, these mice displayed loss of patellae. This outcome can be applied to humans and explain the small, improperly shaped, or completely absent patellae that are seen in NPS patients because of LMX1B mutations (McIntosh et al., 2005). Additionally, due to these mutations, Sox9 and Scx are unable to begin forming the patella as a part of the femur. This also leads to problems with joint formation since this process depends on the expression of Sox9 in the patella cells. This allows for the differentiation of the patella cells from the interzone cells, which generates joint cells in these interzone cells (Eyal et al., 2015). Furthermore, the positioning of tendons and ligaments around these joints provides reasoning for patella hypoplasia found within NPS. The absence of LMX1B expression from the surrounding muscle progenitors causes the patella hypoplasia since the muscle cells are unable to migrate into the correct position within the limb bud. Thus, this dramatically affects the connections that are supposed to be normally formed among the tendons and ligaments because the muscle is not in the right position (McIntosh et al., 2005).
Along with this, recurring dislocation of the patella is common in patients with NPS, and this is connected to poor development of the vastus medialis muscle. The vastus medialis muscle is one of the four quadriceps muscles and aids in stabilizing the patella when the knee is bent (Sweeney et al., 2003). Also, the lack of LMX1B expression impacts the spread of the motor axons of the lateral motor column (LMC). The LMC stretches over the brachial and lumbar regions of the spinal cord and is composed of motor neurons within the limbs. Usually, the axons at the base of the limb branch to form a lateral segment that migrates into the dorsal limb. When LMX1B undergoes a mutation, then the migration of the lateral segment becomes random, thus impacting the dorsal limb structures, like the patella (McIntosh et al., 2005).
Utilizing this same reasoning, this also helps to explain the abnormalities viewed in the elbows and hips of NPS patients. Since the LMX1B gene is nonfunctional, then this means that the dorsal positioning of the cells within the radial head cannot be properly distributed. As a result, this leads to hypoplasia and potential for dislocation of the radial head, which was similarly seen with patella hypoplasia and dislocation. This connection between the two indicates that the deformities are due to the mutations in LMX1B (Witzgall, 2017). Additionally, the formation of iliac horns results from the nonfunctional LMX1B gene as well. The disruption of dorsal positioning within the iliac crest cells causes incorrect positioning of the mesenchyme cells. Then, when the iliac crest undergoes further development, excess bone extends and provides the horn-like projections (Sweeney et al., 2003). Furthermore, the formation of iliac horns is connected with poor development of the gluteus medius muscle, like with the vastus medialis muscle for the patella. Again, this is due to the absence of LMX1B expression from surrounding muscle progenitors (McIntosh et al., 2005). Lastly, the nail deformities are also due to mutations in LMX1B expression, which leads to a deficiency in the differentiation and specification of dorsal cells. Primarily, individuals with NPS exhibit nails that are either underdeveloped or completely absent. These are the main symptoms in the patellae as well, thus highlighting the importance of LMX1B on dorsal positioning (Sweeney et al., 2003).
Not only does NPS produce defects within the nails and skeletal system, but it can also affect important organs of the body, specifically the kidneys and eyes. It has been shown that LMX1B expression is needed for the differentiation of podocytes, which are cells within the Bowman’s capsule in the kidneys, since kidney failure led to death in knockout mice that were generated without LMX1B (Witzgall, 2017). This gene is even necessary after podocytes have completely differentiated because LMX1B has been identified in the glomerulus. The kidney phenotypes among the knockout mice share similarities with human kidney biopsies of NPS patients, which included excess splitting and thickening of the glomerular basement membrane (GBM). The GBM is the basal lamina layer of the glomerulus in the kidney and helps in separating the blood from the filtrate. Although mortality is uncommon for patients with NPS, it occurs when there are severe abnormalities within the podocytes and GBM. This results in kidney failure since the kidneys can no longer filter the waste products from the blood (McIntosh et al., 2005). Within the eye, it has been shown that LMX1B expression takes place in the periocular mesenchyme and trabecular meshwork. The periocular mesenchyme develops into the sclera and cornea, while the trabecular meshwork drains the aqueous humor from the eye. When LMX1B is mutated, this inhibits the functions of the periocular mesenchyme and trabecular meshwork. Due to this, high pressure forms within the eye, which then damages the optic nerve and results in glaucoma (McIntosh et al., 2005). Since glaucoma is able to be controlled, it should be tested for in all individuals with NPS as a precaution. The deformity within the collagen of the cornea is similar to that of the kidney, thus indicating a potential role of collagen regulation in LMX1B (Sweeney et al., 2003).
In conclusion, NPS is primarily caused by loss of function mutations in the LMX1B gene, which causes a disruption in dorsal cell positioning. Although the main symptoms of NPS deal with abnormalities found within nails and patellae, NPS also can affect elbows, hips, eyes, and kidneys. This displays the pleiotropic nature of this birth defect, and this provides the opportunity to analyze the impact of gene interactions on human development (Sweeney et al., 2003). However, further research can still be conducted on this topic, specifically examining the relationship between NPS and sexual development. Due to the LMX1B mutations, this also inhibits the expression of Sox9 and Scx progenitor cells in the patella. Sox9 also plays a crucial role in male sex determination by working with Fgf9 to inhibit ovary formation by preventing -catenin from entering the nucleus. Due to this, further research should analyze whether or not male patients with NPS also suffer from problems in their sexual development as well. These problems could potentially deal with the development of female secondary sex characteristics in those individuals who are genetically male (Gilbert and Barresi, 2016). By exploring this concept, this would further broaden the scope and impact of NPS.
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