(no subject)
I have only been awake for 26 hours.
I have only finished 6 lab organic chemistry lab reports
I have only read 3 chapters of genetics
I have only written 1 perfect biochemistry term paper
Understanding the biochemistry of inborn errors of metabolism significantly increases the opportunity to improve the health of affected individuals. Smith-Lemli-Opitz syndrome (SLOS) is a common inborn error of metabolism. Statistical data shows the prevalence to be approximately 1 in 20,000 births with a carrier frequency ranging from 1 to 2% in North American Caucasian populations1. SLOS is an autosomal recessive disease. It follows that both parents of affected individuals must be carriers of the gene. The syndrome results in multiple physical abnormalities and severe mental retardation. The determined error of metabolism that occurs is the absence or deficiency in the enzyme that catalyzes the final step of cholesterol synthesis, the 7-dehydrocholesterol reductase enzyme1. Seeing that cholesterol is required in the processes of every human cell, many developmental abnormalities are presented with the inhibition of cholesterol synthesis observed with SLOS. The biochemical determinant for diagnosis of patients is the decreased plasma cholesterol levels and increased concentrations of 7-DHCR, which is determined using gas chromatography and mass spectrometry techniques. The gene for 7-DHCR was recently mapped to chromosome 11q12-13 and common mutations were found in most patients7. Growing up with an affected younger brother, this paper has presented the opportunity to further explore the causes of the syndrome in addition to being exposed to the current research and therapy that is developing for SLOS patients.
Characteristic symptoms of SLOS range in severity and expressivity. Common physical abnormalities include growth retardation, syndactyly of the second and third toes, genital malformations, clubfeet, cataracts and cleft palate. Mental retardation is present in all patients in addition to retarded or no speech development. Furthermore, behavioural difficulties such as violent outbursts and self-destructive habits are common7. The less severe form of the syndrome is termed type I SLOS where as the more severe and often lethal form is termed type II SLOS.
Conclusive evidence shows that Smith-Lemli-Opitz syndrome is caused through a defect in the enzyme that reduces 7-dehydrocholesterol to cholesterol. This causes a reduction in the plasma cholesterol levels in affected individuals and an increase in the 7-dehydrocholesterol concentrations . Through DNA sequencing it was discovered that thirteen distinct common mutations occurred in patients. The investigation of mutations was centered on exons and their splice sites. In the study of thirteen patients with SLOS by Fitzky et al., five common mutations existed among all of the affected individuals2. The majority of the mutations were found to be missense mutations. For example, the missense mutations in L99P and L157P introduce proline residues in putative transmembrane alpha helices, and the mutation in A242V impairs protein folding . The missense mutation in L44P changes a leucine to a proline and affects the functionality of the endoplasmic reticulum. All of said missense mutations effectively reduce successful protein expression. Mutations exist that cause a shift in the reading frame or introduce a premature stop codon, which were termed to be null alleles. These mutations were all determined to decrease the catalytic activity of the 7-DHCR gene or destroy it entirely. Altogether this data suggests that SLOS is a direct effect of a mutation in the 7-DHCR gene for various reasons, the obvious reason being that none of the aforementioned mutations were found in more than eighty percent of the healthy control groups2.
In a study conducted in 1998 by Honda et al1., it was hypothesized that the cholesterol deficiency experienced by SLO patients was a direct result of the effect of excess 7-dehydrocholesterol suppressing the HMG-CoA reductase activity. The HMG-CoA reductase pathway is a cellular process that results in cholesterol production. In the study both control and SLOS affected fibroblast were placed in the same medium. After one day, an equal up-regulation of HMG-CoA reductase activity was observed from both groups. However, after seven days of gestation, and by increasing the amount of 7-dehydrocholesterol concentration in the control sample, the activity observed was similar to that of SLOS patients; the HMG-CoA reductase activity was reduced to a greater extent. Statistical data showed patient’s total plasma sterol concentration, 85 mg/dl, was well below the 5th centile for plasma cholesterol levels in age-matched controls1. The conclusion could then be drawn that the 7-dehydrocholesterol provides significant inhibition of the HMG-CoA reductase pathway and that the 7-DHCR enzyme “down-regulates cholesterol biosynthesis at the level of HMG-CoA reductase1.”
Due to the fact that that this inborn error of metabolism impairs morphogenesis, the formation and differentiation of an organism and its parts, the distinguishable characteristics range greatly in expressivity, variety and severity. Affected individuals are usually characterized as either type I or type II. Essentially the type II patients exhibit the more severe symptoms and physical abnormalities. Through case studies conducted on both type I SLOS and type II SLOS patients it was determined that there is a correlation between the severity of the disease and the type of mutation that occurs. The patients diagnosed with “SLO syndrome type I were heterozygous for missense mutations that result in mutated 7-DHCR proteins that still may have sufficient residual activity to support life. On the other hand, the homozygous 134-bp insertion found in the patients with SLO syndrome type II produces a truncated 7-DHCR protein lacking 154 amino acids of its original C-terminal sequence .” This resulting protein was deemed to be non functional. Therefore it is evident that the phenotypic expression is variable and often determined by the type of mutation present.
Smith-Lemli-Opitz Syndrome has been extensively researched and the majority of the biochemistry associated with the condition is thoroughly understood and well documented. However, in 2006 a study was performed to determine the role of 7-DHCR in neural development. In this study by Tadjuidje et al ., the molecular characterization of 7-DHCR from Xenopus laevis was reported. It was found that the expression of the specific reductase was isolated to the Spemann’s organizer and later to the notochord. “The data from the over expression and knockdown experiments revealed that a tight control of cholesterol synthesis is particularly important for proper development of the central and peripheral nervous system.5”
Additionally, studies are continually conducted to further improve pre-natal detection of the syndrome. One such study carried out in 2006 by Jezela-Stanek et al . examined the urinary excretions of high-risk mothers. In the resultant SLOS positive cases the urine concentration of 7-DHPT/PT was notably higher than in the SLOS negative cases. The drawback concerning the findings of this study is that cholesterol production in the uterus is not detectable until approximately eight weeks into the gestation period. Therefore, the test is not effective until the eleventh or twelfth week of pregnancy. However, early detection does open the door for possible prenatal treatment. In a study done by Malgorzata et al . maternal cholesterol supplementation was administered in hopes of reducing the severity of the symptoms. Nevertheless, due to the variance in the expressed severity of the syndrome the effectiveness of the treatment was difficult to gauge.
Recent studies are being conducted on mice following the identification of a full-length cDNA coding for mouse 7-DHCR4. From this sequence mice will be modeled with SLOS. This model makes it possible for researchers to experiment various cholesterol therapy methods through varying the content of cholesterol administered. This research is directed towards determining the causation of the varying phenotypes of SLOS patients.
Through further understanding of the path physiology of SLOS benefits become apparent to SLOS patients, and additional insight is offered in respect to the role of cholesterol metabolism for various other genetic diseases. Due to the increased accuracy of detection for SLOS, in the future automatic maternal serum screening may be administered even for families that do not exhibit a genetic predisposition to the disease. Early detection through the promotion of increased awareness within the scientific community generates hope for the reduction of the severity of the symptoms associated with the syndrome. Due to the advancements in biochemistry and genetics over the past twenty years the comprehension, diagnosis and treatment methods for Smith-Lemli-Opitz syndrome have increased and aided in the understanding and development of new viable treatment options for affected patients.
there is only 4 inches of snow outside
this is the first day in my existance in which i have had the "pleasure" of "enjoying" a snow day
after living in canada for over 17 years and going to school after 8 inches of snow and a windchill of -150 F... this is my first snow day ever
thank you University of Oklahoma
thank you
i think i might attempt to go for a drive
as i am out of smokes
anyone advise against said activity?
i also downloaded the first season of arrested development and am dead set on watching it after my stinking genetics test is over
I have only finished 6 lab organic chemistry lab reports
I have only read 3 chapters of genetics
I have only written 1 perfect biochemistry term paper
Understanding the biochemistry of inborn errors of metabolism significantly increases the opportunity to improve the health of affected individuals. Smith-Lemli-Opitz syndrome (SLOS) is a common inborn error of metabolism. Statistical data shows the prevalence to be approximately 1 in 20,000 births with a carrier frequency ranging from 1 to 2% in North American Caucasian populations1. SLOS is an autosomal recessive disease. It follows that both parents of affected individuals must be carriers of the gene. The syndrome results in multiple physical abnormalities and severe mental retardation. The determined error of metabolism that occurs is the absence or deficiency in the enzyme that catalyzes the final step of cholesterol synthesis, the 7-dehydrocholesterol reductase enzyme1. Seeing that cholesterol is required in the processes of every human cell, many developmental abnormalities are presented with the inhibition of cholesterol synthesis observed with SLOS. The biochemical determinant for diagnosis of patients is the decreased plasma cholesterol levels and increased concentrations of 7-DHCR, which is determined using gas chromatography and mass spectrometry techniques. The gene for 7-DHCR was recently mapped to chromosome 11q12-13 and common mutations were found in most patients7. Growing up with an affected younger brother, this paper has presented the opportunity to further explore the causes of the syndrome in addition to being exposed to the current research and therapy that is developing for SLOS patients.
Characteristic symptoms of SLOS range in severity and expressivity. Common physical abnormalities include growth retardation, syndactyly of the second and third toes, genital malformations, clubfeet, cataracts and cleft palate. Mental retardation is present in all patients in addition to retarded or no speech development. Furthermore, behavioural difficulties such as violent outbursts and self-destructive habits are common7. The less severe form of the syndrome is termed type I SLOS where as the more severe and often lethal form is termed type II SLOS.
Conclusive evidence shows that Smith-Lemli-Opitz syndrome is caused through a defect in the enzyme that reduces 7-dehydrocholesterol to cholesterol. This causes a reduction in the plasma cholesterol levels in affected individuals and an increase in the 7-dehydrocholesterol concentrations . Through DNA sequencing it was discovered that thirteen distinct common mutations occurred in patients. The investigation of mutations was centered on exons and their splice sites. In the study of thirteen patients with SLOS by Fitzky et al., five common mutations existed among all of the affected individuals2. The majority of the mutations were found to be missense mutations. For example, the missense mutations in L99P and L157P introduce proline residues in putative transmembrane alpha helices, and the mutation in A242V impairs protein folding . The missense mutation in L44P changes a leucine to a proline and affects the functionality of the endoplasmic reticulum. All of said missense mutations effectively reduce successful protein expression. Mutations exist that cause a shift in the reading frame or introduce a premature stop codon, which were termed to be null alleles. These mutations were all determined to decrease the catalytic activity of the 7-DHCR gene or destroy it entirely. Altogether this data suggests that SLOS is a direct effect of a mutation in the 7-DHCR gene for various reasons, the obvious reason being that none of the aforementioned mutations were found in more than eighty percent of the healthy control groups2.
In a study conducted in 1998 by Honda et al1., it was hypothesized that the cholesterol deficiency experienced by SLO patients was a direct result of the effect of excess 7-dehydrocholesterol suppressing the HMG-CoA reductase activity. The HMG-CoA reductase pathway is a cellular process that results in cholesterol production. In the study both control and SLOS affected fibroblast were placed in the same medium. After one day, an equal up-regulation of HMG-CoA reductase activity was observed from both groups. However, after seven days of gestation, and by increasing the amount of 7-dehydrocholesterol concentration in the control sample, the activity observed was similar to that of SLOS patients; the HMG-CoA reductase activity was reduced to a greater extent. Statistical data showed patient’s total plasma sterol concentration, 85 mg/dl, was well below the 5th centile for plasma cholesterol levels in age-matched controls1. The conclusion could then be drawn that the 7-dehydrocholesterol provides significant inhibition of the HMG-CoA reductase pathway and that the 7-DHCR enzyme “down-regulates cholesterol biosynthesis at the level of HMG-CoA reductase1.”
Due to the fact that that this inborn error of metabolism impairs morphogenesis, the formation and differentiation of an organism and its parts, the distinguishable characteristics range greatly in expressivity, variety and severity. Affected individuals are usually characterized as either type I or type II. Essentially the type II patients exhibit the more severe symptoms and physical abnormalities. Through case studies conducted on both type I SLOS and type II SLOS patients it was determined that there is a correlation between the severity of the disease and the type of mutation that occurs. The patients diagnosed with “SLO syndrome type I were heterozygous for missense mutations that result in mutated 7-DHCR proteins that still may have sufficient residual activity to support life. On the other hand, the homozygous 134-bp insertion found in the patients with SLO syndrome type II produces a truncated 7-DHCR protein lacking 154 amino acids of its original C-terminal sequence .” This resulting protein was deemed to be non functional. Therefore it is evident that the phenotypic expression is variable and often determined by the type of mutation present.
Smith-Lemli-Opitz Syndrome has been extensively researched and the majority of the biochemistry associated with the condition is thoroughly understood and well documented. However, in 2006 a study was performed to determine the role of 7-DHCR in neural development. In this study by Tadjuidje et al ., the molecular characterization of 7-DHCR from Xenopus laevis was reported. It was found that the expression of the specific reductase was isolated to the Spemann’s organizer and later to the notochord. “The data from the over expression and knockdown experiments revealed that a tight control of cholesterol synthesis is particularly important for proper development of the central and peripheral nervous system.5”
Additionally, studies are continually conducted to further improve pre-natal detection of the syndrome. One such study carried out in 2006 by Jezela-Stanek et al . examined the urinary excretions of high-risk mothers. In the resultant SLOS positive cases the urine concentration of 7-DHPT/PT was notably higher than in the SLOS negative cases. The drawback concerning the findings of this study is that cholesterol production in the uterus is not detectable until approximately eight weeks into the gestation period. Therefore, the test is not effective until the eleventh or twelfth week of pregnancy. However, early detection does open the door for possible prenatal treatment. In a study done by Malgorzata et al . maternal cholesterol supplementation was administered in hopes of reducing the severity of the symptoms. Nevertheless, due to the variance in the expressed severity of the syndrome the effectiveness of the treatment was difficult to gauge.
Recent studies are being conducted on mice following the identification of a full-length cDNA coding for mouse 7-DHCR4. From this sequence mice will be modeled with SLOS. This model makes it possible for researchers to experiment various cholesterol therapy methods through varying the content of cholesterol administered. This research is directed towards determining the causation of the varying phenotypes of SLOS patients.
Through further understanding of the path physiology of SLOS benefits become apparent to SLOS patients, and additional insight is offered in respect to the role of cholesterol metabolism for various other genetic diseases. Due to the increased accuracy of detection for SLOS, in the future automatic maternal serum screening may be administered even for families that do not exhibit a genetic predisposition to the disease. Early detection through the promotion of increased awareness within the scientific community generates hope for the reduction of the severity of the symptoms associated with the syndrome. Due to the advancements in biochemistry and genetics over the past twenty years the comprehension, diagnosis and treatment methods for Smith-Lemli-Opitz syndrome have increased and aided in the understanding and development of new viable treatment options for affected patients.
there is only 4 inches of snow outside
this is the first day in my existance in which i have had the "pleasure" of "enjoying" a snow day
after living in canada for over 17 years and going to school after 8 inches of snow and a windchill of -150 F... this is my first snow day ever
thank you University of Oklahoma
thank you
i think i might attempt to go for a drive
as i am out of smokes
anyone advise against said activity?
i also downloaded the first season of arrested development and am dead set on watching it after my stinking genetics test is over