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Boston University School of Medicine, USA, Email: [email protected] Citation Download PDF. To date, 31 genes associated with different forms of SCA have been but the cellular and molecular bases for this pathology remain poorly deﬁned. The autosomal dominant cerebellar ataxias (ADCA) were thought to be. X-linked trait synonyms, X-linked trait pronunciation, X-linked trait translation, English dictionary definition of X-linked trait. adj. Of, relating to, or characterized by. If you want to date exclusively then it changes. It's whatever you want to call it. We all have a different meaning for somethings & dating is one of.
Known Etiological Factors Although it has frequently been indicated that the causes of essential hypertension are not known, this is only partially true because we have little information on genetic variations or genes that are over-expressed or under-expressed as well as the intermediary phenotypes that they regulate to cause high BP Luft, A number of factors are known to increase BP, including 1 obesity, 2 insulin resistance, 3 high alcohol intake, 4 high salt intake in salt—sensitive patients5 aging 6 sedentary lifestyle, 7 stress, 8 low potassium intake, and 9 low calcium intake Sever, Furthermore, many of these factors are additive, such as obesity and alcohol intake.
Some of these factors have inherited, behavioral, and environmental components. Recognition of the hypertensinogenic factors may allow non-pharmacological intervention.
Hypertensinogenic factors have an important genetic component. Furthermore, there are interactions between genetic and environmental factors, which in turn influence intermediary phenotypes such as sympathetic nerve activity, the renin-angiotensin-aldosterone and renal kallikrein-kinin systems, and endothelial factors, which in turn influence other intermediary phenotypes such as sodium excretion, vascular reactivity, and cardiac contractility.
These and many other intermediary phenotypes determine total vascular resistance and cardiac output and, consequently, BP. Thus recognition of factors that induce hypertension is not only of theoretical but also of practical importance. Genetic factors also influence behavioral patterns, which might lead to BP elevation. For example, a tendency toward obesity or alcoholism will be influenced by both genetic and environmental factors.
Mutations in at least 10 genes have been shown to raise or lower BP through a common pathway by increasing or decreasing salt and water reabsorption by the nephron Lifton, Glucocorticoid — Remediable Aldosteronism This is an autosomal dominant form of monogenic hypertension in which aldosterone secretion is regulated by adrenocorticotropic hormone.
Glucocorticoid treatment causes BP to decrease and gives the syndrome its name. The patients are usually thought to have primary aldosteronism because they exhibit volume expansion, metabolic alkalosis with hypokalemia, low plasma renin, and high aldosterone. However, with the development of direct genetic testing, the BP of patients with this syndrome has been found to cover a wide range, including normotensive levels Gates et al, The BP would be the combined result of the inherited BP including the genetic mutation and the increase in BP caused by hypertensinogenic factors such as salt.
It is characterized by the early onset of hypertension with hypokalemia and suppression of both plasma renin activity and aldosterone, the latter differentiating this syndrome from primary aldosteronism. It is also possible that high BP in blacks, who are frequently salt—sensitive, is due to a polymorphism in one of the sodium channel genes or in one of the genes of systems that regulate it, causing its activity to increase.
Normally this enzyme converts cortisol to the inactive metabolite cortisone. In the distal nephron, this is important because cortisol and aldosterone have a similar affinity for the mineralocorticoid receptor. The enzymatic deficiency allows the mineralocorticoid receptors in the nephron to be occupied and activated by cortisol, causing sodium and water retention, volume expansion, low rennin, low aldosterone, and more importantly, a salt-sensitive form of hypertension.
Thus this gene may be a locus for salt-sensitive essential hypertension. Affected persons are shorter than non-affected relatives. The gene for hypertension has been mapped to the short arm of chromosome 12 12p in a Turkish kindred, although the gene responsible for this syndrome has not yet been cloned. Unlike the other 3 autosomal forms of hypertension, BP is not affected by volume expansion and the underlying mechanism is not known.
Thus, identification of the gene responsible may help clarify some of the genetic alterations in this form of essential hypertension. Obesity and Insulin Resistance The mechanism by which obesity raises BP is not fully understood, but increased BMI is associated with an increase in plasma volume and cardiac output; both these alterations and BP can be decreased by weight loss in both normotensive and hypertensive subjects Rocchini et al,even when sodium intake is kept relatively constant Reisin et al, Exercise decreases plasma insulin by a different mechanism than loss of body weight.
Furthermore, non-obese hypertensive subjects are much more likely to exhibit insulin resistance than normotensive individuals Modan et al, Insulin by itself has a vasodilator effect.
Insulin — like growth factor I Diez,and leptin, a neuropeptide that regulates appetite, have also been implicated in the pathogenesis of obesity — induced hypertension. Thus, although the mechanisms by which obesity and insulin resistance increase BP remain undefined, it is clear that these increases in BP are overlain on the inherited BP.
A reasonable generalized approach for all patients includes 1 weight loss for the overweight patient; 2 regular physical activity; 3 moderation of alcohol consumption; 4 dietary modification to reduce sodium and fat and increase calcium, potassium, magnesium, vitamins, and fiber from food sources; and 5 cessation of smoking.
Such an approach has been shown to produce significant sustained reductions in BP while reducing overall cardiovascular risk. The Saudi population can be characterized by a specific ethnic subset which presumably reflects a unique set of allele frequencies and genotypes and that could differentiate them from other population in near geographical areas and worldwide i. Therefore, this study was conducted to investigate the genetic variation of populations from Saudi Arabia by using 15 autosomal STR markers - currently used in forensic and paternity testing.
DNA was collected from a sample of unrelated volunteers residing in the central region Riyadh Province of Saudi Arabia.
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The allele frequencies of the 15 STR markers were calculated using gene counting methods and compared with frequencies from other populations previously studied. Thus, first and second cousins are not included in the study. The age of the study population ranged between 10 and 45 years median of 25 at the time of blood collection.
There were For quality assurance purposes, multiple DNA samples with known combined STR genotypes were run in parallel with our study samples and appropriate results were obtained for these control samples on every occasion. Statistical analysis The allele frequencies were calculated based on the number of the detected alleles for each specific locus. An overall significance level for testing HWE hypothesis was set at 0.
Software to determine the genetic differences and similarities between this study sample and published data from other populations [ 11 ]. Results and Discussion The 15 autosomal STR loci from all samples tested were amplified successfully. However, EIF4G1 is not considered a common risk factor for Parkinson's disease at least in the European cohorts [ ]. HLA region vA genome-wide association study of 2, Parkinson's disease patients from North America identified a novel risk factor in HLA region [ ] replicated in a French cohort [ ].
A functional hypothesis of HLA involvement in PD pathogenesis is via gene regulation [ ] or chronic inflammation [ ]. GBA mutations were reported in early onset PD with higher incidence in Jews families and represent an important risk factor for PD in this population [ ]. The GBA mutations carrier frequency estimated at Comorbidity of PD and Gaucher disease was also noted [ ]. The clinical expression is variable ranging from a mild L-dopa responsive idiopathic PD phenotype and Lewy body dementia [ ].
The proposed theories which confer increased risk of Parkinsonism to Gaucher carriers include gainof- function of mutant glucocerebrosidase proteins associated with deficiency in the autophagic-lysosomal pathway [ ].
MAPT The gene localized on chromosome 17q21 codes for microtubuleassociated protein tau MAPTa phosphorylated protein with essential role in maintaining the integrity of the cytoskeleton and axonal transport in neurons [ ]. Genomic screen of individuals from families yielded significant evidence of association for allelic and haplotype association with tau [ ].
LP multiplies by 9 the risk to develop PD.
These findings were replicated in Ashkenazi Jewish population [ ] but not in an Asian cohort [ ]. Two more families with different homozygous DNAJC6 mutations segregating with PD and different phenotype with slow disease progression and dopa-sensibility were identified recently [ ].
RAB39B A large deletion including RAB39B gene led to identification of a causal relationship with early-onset Parkinsonism and intellectual disability in 3 members of an Australian kindred with X-linked dominant transmission. The same phenotype was described in an unrelated Wisconsin family presenting a missense mutation in RAB39B [ ]. A novel missense mutation in the RAB39B gene was identified in a large family with a mean age at onset of MACF1 is active during brain development by regulating microtubule dynamics signaling in order to determine neuronal positioning [ ].
TMEM Very recently, another gene with role in synaptic vesicle trafficking involved in pathogenesis of PD was identified on chromosome 20pter-p12 [ ]. VPS13C Genetic findings strongly suggest that VPS13C vacuolar protein sorting 13C mutations may contribute to early-onset Parkinsonism with severe phenotype including cognitive deterioration and accelerated disease progression.
VPS13C is a protein of mitochondrial membrane with role in maintaining of mitochondrial membrane potential and conformation [ ]. PODXL An implication of a neurodevelopmental pathway in pathogenesis of PD is supporting by the genetic analysis of two affected siblings that harbor a homozygous frameshift mutation, in PODXL podocalyxin-like genea neural adhesion molecule, located on chromosome 7q [ ].
Synphilin-IA might constitute a genetic risk factor for the development of parkinsonism seen that a putative mutation has been identified as segregating with PD in two patients with late-onset PD [ ].
Tyrosine hydroxylase The genome-wide association study found a deletion in tyrosine hydroxylase, enzyme involved in dopamine synthesis, in one adult PD [ ] whereas missense mutations in tyrosine hydroxylase gene were already involved in infantile parkinsonism [ ]. Advances in genetic field especially in Mendelien's forms of PD have given insights into molecular mechanisms critical to develop new disease-modifying therapies.
Recent data provide evidence for new molecular pathways involving neurodevelopmental mechanisms , modulating the signaling processes at the endocytic pathway [ ], synaptic vesicles endocytosis and trafficking in PD pathogenesis , maintaining the integrity of the cytoskeleton and axonal transport in neurons [ ].
Genes' Products Relations and Mechanisms Implicated in Mendelien's forms of PD The interactions among genes' products may be an important event of molecular mechanisms involved in the pathogenesis of PD. These multiples protein substrates are intervening in a fine tuning molecular system in order to provide normal dopaminergic cells function.
In favor of the mitochondrial dysfunction plead the identification of pathological cells harboring large quantities of mitochondrial DNA deletions [ ].
A hypothesis which has been advanced to explain the mitochondrial dysfunction when parkinsonian features were signaled in designer drug abusers [ ] was the inhibitory effect of MPTP on mitochondrial complex 1 of the electron transporter chain [ ], functionally linked with mitochondrial DNA mutations , sustained by the extrapyramidal phenotype induction in animal models by inhibitors of mitochondrial complex l [ ].
VPS13C as a mitochondrial membrane protein interacts with PINK1 and Parkin in order to provide the mitochondrial morphology and membrane potential integrity [ ].
Mechanisms Implicated in Parkinson Disease from Genetic Perspective
Beside mitochondrial dysfunction, the impaired pathways involved in clearing abnormal cellular proteins and damaged organelles, the ubiquitin-proteasome system and the autophagic pathway involving lysosomal activity [ 30] play a crucial role in PD etiology. Lysosomal storage disorders such as Gaucher disease have a possible functional link with PD through participation of parkin at the degradation of mutant glucocerebrosidase [ ]. Beside glucocerebrosidase, another lysosomal enzyme SMPD1 intervene in maintaining the lysosome-mediated autophagy normal function [ ].
Parkin and PINK1 functions are strictly linked in key molecular pathways to provide mitochondrial function and morphology regulation [ 52 ] by stimulating fission and inhibiting fusion [ 76] and eliminate damaged mitochondria through mitophagy [ ].
Parkin mutations altered mitophagy and PINK1 mutations the degradation of damaged mitochondria [ 53 ] that possess neurotoxic effect [ ].
VPS35 genetically and functionally interacts with parkin in order to provide mitochondrial homeostasis [ ] and with EIF4G1 in order to prevent accumulation of dysfunctional proteins and therefore neurotoxicity [ ]. PINK1 recruit parkin through phosphorylation of ubiquitin in order to eliminate the impaired mitochondria [ ]. Surprisingly, the triple inactivation of genes of parkin, DJ-1 and PINK1 did not disturb the function and morphology of dopaminergic cells nor diminish the levels of dopamine.
Therefore is clear that inactivation of these PD genes involved in autosomal recessive transmission is not sufficient to induce nigral degeneration and not indispensable for the survival [ ]. Most of the sporadic cases of PD do not have a clear genetic etiology and GWAS availability is limited by the insufficiency of the significant effect size risk alleles [ ].
However, even a modest effect on PD risk is noted for each variant taken alone, their global effect could have a significant impact [ ]. Confirmation by high-throughput sequencing of loci already implicated in PD pathogenesis with increased risk for late onset PD supports the idea that familial disease are etiologically related to sporadic PD because of the functional equivalence among genes with common risk variants and rare familial PD mutations. Therefore, pathogenesis of PD is based upon interaction between genetic susceptibility and the environmental exposure.
Multiple environmental factors inducing oxidative stress and mitochondrial damage coupled to impairment of molecular mechanisms concerning the neuroprotective and autophagic activities shall be responsible for dopaminergic neurons death. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of more adequate biomarkers and potent therapies with neuroprotective effects.
N Engl J Med Gowers W A manual of diseases of the nervous system. Parkinson disease in twins: J Am Med Assoc International Human Genome Sequencing Consortium Finishing the euchromatic sequence of the human genome. Proc Natl Acad Sci Volles MJ, Lansbury PT Jr Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism.
Nat Rev Neurosci 3: J Biol Chem Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Commun Integr Biol 3: