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Specific alterations in FBN1 gene leads to different clinical outcomes as observed in Marfan lipodystrophy and geleophysic dysplasia 2
Fibrillin is an essential structural component found in connective tissue1. Humans have three types of fibrillin that are highly conserved and have similar structures—fibrillin 1, 2, and 31. These three types of fibrillin polymerize into microfibrils and therefore able to function in regulatory and structural roles in the extracellular matrix1. Microfibrils are found widely throughout the body in elastic and nonelastic connective tissues2. Specifically, fibrillin can be found in the connective tissue of the skin, vasculature, cartilage, tendon, muscle, lung, kidney, cornea, and cilary zonule2. Several different proteins associate with microfibrils by directly interacting with fibrillin, such as bone morphogenetic proteins1. Mutations in fibrillin or the associated proteins can lead to genetic disorders. There have been several genetic disorders associated with mutations in fibrillin 1 with a range of diverse phenotypes.
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Fibrillin 1 is encoded by the FBN1 gene found on chromosome 15 and contains 65 exons2. Fibrillin 1 is observed in organs, provides structural support, and is predominately found in adult microfibrils2. Structurally, fibrillin has five distinct regions—46 EGF-like repeats that are interrupted by 8 cysteine rich motifs, a region of basic residues by the amino-terminal, another cysteine-rich region, the carboxy terminus, and a proline-rich domain2. Fibrillin 1 can form homodimers in the presence of calcium that are supported through disulfide bonds2. Important proteins in fibrillin 1 microfibril assembly are the ADAMTS proteins2,3.
A widely studied disorder associated with mutations in FBN1 is Marfans syndrome. Some common symptoms of Marfans syndrome include problems with eyes, heart, and lungs, long bones that are overgrown, and decreased muscle and subcutaneous fat11. Researchers have found more than 3000 mutations in FBN1 that are known to cause Marfan syndrome1. These mutations are vast as they occur in 56 of the 65 exons in FBN12. Molecularly some patients had approximately half the amount of fibrillin synthesized while others maintain normal synthesis but had abnormal secretion of fibrillin11. Additionally, patients that had normal synthesis and secretion may not be able to incorporate fibrillin properly into the ECM11. Mutations associated with other exons are rarer and are phenotypically distinct2. Two disorders associated with FBN1 mutations and vary phenotypically are Marfan lipodystrophy and geleophysic dysplasia 2.
In Marfan lipodystrophy, patients share some similar symptoms with Marfan syndrome, but not all6. In general, patients are tall but do not gain weight properly such that their growth rate in height is disproportionate to their weight gain4. Patients also have characteristic facial features including downslanting palpebral fissues and retrognathia, hyperextensibility of abnormally long fingers and toes, myopia, widening of dural sac around spinal cord and a progeroid appearance although these individuals are not prematurely aging4. Only some patients suffer from heart-related conditions-such as dilation of the aortic root2.
Although geleophysic dysplasia 2 has mutations in the FBN1 gene, it has vastly different clinical outcomes than Marfan lipodystrophy. Instead of tall stature, patients are short with a full ‘happy’ face and wide spaced eyes2. Compared to Marfan lipodystrophy, patients suffer from more serious heart conditions including problems with their mitral, tricuspid, and aortic valves2. These heart conditions are often fatal in these patients2. The skeletal system of these patients also has decreased joint mobility and short tubular bones2. Considering the vast phenotypic differences between Marfan lipodystrophy and geleophysic dysplasia 2, it is quite intriguing that both diseases stem from mutations within the same gene—FBN1.
Marfan lipodystrophy syndrome is quite rare and only a small population of patients have been diagnosed and studied. In general, patients with Marfan lipodystrophy syndrome display heterozygous mutations in exon 64 of the FBN1 gene5. Some patients have deletions that lead to frameshift mutations creating premature stop codons5. These deletions vary in size as one patient was reported to have a 2 base pair deletion while another patient had a 20 base pair deletion5. Other patients have splice site transversions5. Interesting in some patients, this introduced mutation was de novo and was not previously seen in the parents of the respective patients5. It is curious how certain mutations in this specific exon can lead to a distinct disorder from classic Marfan syndrome.
Because not all mutations in exon 64 or premature stop codons produce Marfan lipodystrophy, it is especially intriguing to further study how the structure and function of fibrillin 1 is altered in patients with the genetic disorder6. Patients with Marfan lipodystrophy all have an introduced premature stop codon that have been predicted to evade nonsense-mediated decay (NMD)6. With the ability to bypass NMD, it is predicted that this leads to truncated fibrillin 1 proteins6. I am curious if patients have additional fibrillin 1 production or if all transcripts arising from the mutated gene are able to escape NMD considering the premature stop codon arises in the second to last codon6. Some research has shown that the amount of FBN1 mRNA levels correlates with the amount of adipose tissue in mice and rabbits12,13. It has also been shown in a rabbit model that without the C-terminus, there is reduced secretion and elastin found in the extracellular matrix13.
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This predicted truncated protein also affects a protein recently named asprosin—profibrillin’s C-terminal cleavage product7. Researchers originally found that asprosin is secreted by adipose cells and is transported to the liver where the end result is a rapid increase in blood glucose7. Recently a group of researchers were not able to reproduce Romere’s results thus calling the function of asprosin into further questioning8. Regardless of asprosin’s function, with the premature stop codon introduced with Marfan lipodystophy syndrome, asprosin synthesis may be limited. Subsequent studies have found decreased amounts of asprosin leads to lipodystrophy and a substantial decrease in blood glucose levels in rabbits13. Although the mechanism is not completely clear for Marfan lipodystrophy patients, it is probable that reduced amount in FBN1 mRNA levels, reduced secretion, and a decreased amount of asprosin is essential for this phenotype7,12,13.
Mutations within the FBN1 gene can lead to drastically distinct phenotypic differences as seen in geleophysic dysplasia 2. Autosomal dominant geleophysic dysplasia 2 patients have mutations in the TB5 region in exons 41 and 42 of the FBN1 gene which encode the 5th 8-cysteine domain9,10,15. Mutations were found in essential structural residues or large aromatic regions9. Some mutations introduced a reactive cysteine which could react to outside stimulus or form disulfide bonds within the fibrillin 1 protein2. The addition or loss of a cysteine residue could interrupt disulfide bonds and thus disturb the assembly of fibrillin 1. Mutations involving aromatics could also be deleterious considering disruption of protein folding. Due to misfolding of fibrillin 1, the protein may be aggregating and thus making it difficult to form microfibrils. Subsequently, researchers found that fibrillin 1, with some of these mutations, were able to be secreted into the ECM and incorporate into the microfibril network2. It would be beneficial to know the levels of microfibrils as compared to normal levels for these specific mutations. The mutations that were found in the TB5 region and associated with geleophysic dysplasia 2 have not been previously characterized with Marfan syndrome mutations2.
Additionally, mutations in the ADAMTSLIKE-2 protein were found to cause recessive geleophysic dysplasia9. In a mouse model, ADAMTSLIKE-2 deficient mice did not form microfibrils with fibrillin 114. ADAMTSLIKE-2 affects endochondral ossification thus impairing longitudinal bone growth14. In mice, the absence of ADAMTSLIKE-2 drove aberrant FBN1 levels and led to aggregates near the cell membrane14.
Genetic disorders stemming from mutations in the FBN1 gene can be profoundly phenotypically distinct. Patients with Marfan lipodystrophy are tall with little fat and appear to have prematurely aged whereas patients with geleophysic dysplasia 2 have short tubular bones and have heart problems. Each of the mentioned disorders have genetic mutations in a specific exon(s) in the FBN1 gene. The location of the mutations essentially determines the fate of the patient. In Marfan lipodystrophy, mutations in exon 64 leads to decreased FBN1 mRNA, secretion, and asprosin7,12,13. On the other hand, geleophysic dystrophy 2 has mutations in a cysteine-rich region that may affect the structure and assembly of fibrillin 1 and thus affect longitudinal bone growth14,15. Additionally, aberrant production ADAMTSLIKE-2 protein led to aggregation14. Overall, specific mutations in different regions of the FBN1 gene can lead to different clinical pictures.
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