The neurology landscape is ever changing and dynamic and has been especially influenced by the emergence of modern molecular genetics.
The advancements in modern genetics have been so significant that the identities of more than 350 different pathological genes have been found in less than half a century. More than a thousand different neurologic disorders can be attributed to and genetically mapped to different specific chromosomal locations.
Genetic testing is currently available for several hundred neurologic and psychiatric disorders. A more comprehensive list of these diseases can be found here.
Most of these disorders constitute extremely penetrant mutations resulting in rare neurologic disorders.
Alternatively, there is also the presence of rare monogenic mutations giving rise to common phenotypes. Some examples of these would be
amyloid precursor protein in familial Alzheimer’s disease
microtubule-associated protein tau (MAPT) in frontotemporal dementia
α-synuclein in Parkinson’s disease
These rare monogenic mutations often produce a protein that is also pathogenically involved in the mechanism of illness of the typical, sporadic form. The common pathways via which these two can be linked include abnormal protein processing and eventual protein aggregation and cellular death.
Genome-wide Association Studies
The field of complex genetic disorders is indeed a promising one. There is great hope that the genetic and environmental factors causing the pathology will be amenable to human moderation. Having that in mind, many genome-wide association studies (GWAS) were carried out to identify the many hundreds of variants that increase the risk of disease by at least 1.15 fold. GWAS are dedicated to the theme “common disease, common variant” and only investigate potentially pathogenic alleles that are considered relatively frequent in the population and are present in at least 5 % of the population.
Did you know?
Notable successes among the thousands of GWAS performed to date are the finding of more than 50 risk alleles for multiple sclerosis.
Complementing GWAS with bioinformatics tools enhances the potential to align risk variants in functional biologic pathways, by producing never before seen pathogenic mechanisms and revealing more detailed heterogeneity in a person-specific manner.
Many geneticists, however, are apprehensive about the utility of such Genome-Wide Association Studies. They express doubt that these common disease-associated variants may not explicitly be the pathogenic mutant allele per se, but instead only be an approximate marker of the actual location of the pathogenic mutant allele. This uncertainty paves the way for the next revolution in human genetics conceivable only by virtue of the efficient high-throughput sequencing methodologies. It is now feasible to sequence the entire human genome in as little as an hour with costs incurred to be not more than $4000 for complete coding sequence, or $10 000 in the case of the entire genome. In addition, these costs are expected to decline further. Hence, it is possible to sequence the entire genome of an individual patient and identify the disease-causing variant.
Cost of sequencing the entire human genome coding sequence?
Cost of sequencing the entire human genome?
This method was previously tried on a patient with Charcot-Marie-Tooth neuropathy. The utility of this approach is proven by the successful identification of the exact compound heterozygous mutations in the SH3TC2 gene that were shown to also co-segregate with the disease in other family members.
Gene Dosage Variations
It is a more widely accepted phenomenon that simple changes in the linear nucleotide sequence do not always cause genetic diseases. The architecture of the human genome is much more complex and increasing amounts of information that used to be shrouded in mystery for centuries are now routinely discovered. One of the more prominent themes is that of gene dosage and the association of altered gene copy numbers with genetic diseases.
Our knowledge about the factors that control gene dosage is limited, and hence an ever-increasing field of study. One of the factors suggested so far was “unequal crossing-over”, which can give rise to non-homologous duplications and deletions of segments of chromosome and such inconsistencies account for a staggering 5-10% of the human genome. These segments have a much higher mutational rate than single base pair nucleotides.
Gene dosage abnormalities
Charcot-Marie-Tooth disease type 1A (CMT1A)
Parkinson’s disease (α-synuclein)
Alzheimer’s disease (amyloid precursor protein)
Spinal muscular atrophy (survival motor neuron 2)
Dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1)
Late-onset leukodystrophy (lamin B1)
Developmental neurologic disorders
Schizophrenia
Autism
Epilepsy
It is apparent that copy-number changes contribute considerably to human healthy genomic variation for a multitude of genes implicated in neurologic function, cell growth regulation, and control of metabolism. It is translucent that gene dosage differences will affect numerous behavioral phenotypes, autism spectrum, and learning disorders.
We are still, however, in the primitive stages of understanding the role of gene dosage modulations in human disease. We are bombarded with a chain of confusing and perplexing dilemmas in this field, for which more investigation is required. One such mystery is the X-linked MeCP2 gene. Duplications of X-linked MeCP2 gene causes autism in males but causes anxiety disorder in females instead. On top of that, point mutations in this gene produce the neurodevelopmental disorder Rett syndrome.
Alternative Splicing Variations
Apart from gene dosage, splicing variation is another area that has grown in importance over the years as a contributor to neuropathology. We use the term “alternative splicing” to describe the process of varying the combinations of exons strung into the mature mRNA. This heterogeneity in mature mRNA exon sequence promises an exciting mix of protein products encoded by only a single gene. Alternative splicing is indisputably one of the most powerful ways of manifesting diversity, which is required for sustaining complex functions in the human body. Alternative splicing is used frequently in the nervous system for crucial molecules such as neurotransmitter receptors and ion channels.
The process of faulty alternative splicing is known to be the cause behind numerous diseases. Some examples are
Frontotemporal dementia caused by increased inclusion of exon 10-containing transcripts of MAPT
Duchenne’s myotonic and fascioscapulohumeral muscular dystrophies
Ataxia-telangiectasia
Neurofibromatosis
Inherited ataxia
Fragile X syndrome
It is possible that slight changes in splicing may have far-reaching repercussions and eventually materialise into complex genetic disorders.
Did you know?
A slight splicing variant of interleukin 7 receptor alpha chain produces a more soluble and less membrane-bound receptor, and increases the susceptibility of the patient to multiple sclerosis in many different populations.
Epigenetics Variations
The third field of study that requires further investigation is “epigenetics”. Epigenetics refers to the processes by which cells modulate gene expression by post-genomic alterations whereby the primary genetic sequence of DNA is not changed. DNA methylation and the methylation and acetylation of histone proteins are some of the key aspects of these processes.
Did you know?
One interesting fact about these epigenetic processes is that they seem to be active even in mature non-dividing cells such as the nerve cell, hence hinting at a wider diversity of their utility.
A subset of cells have a clever way of “imprinting” or ensuring that a particular allele,from a particular parent of origin, gets expressed over any other and this is done through mechanisms of epigenetics. The neurodevelopmental disorders Prader-Willi syndrome (mild mental retardation,endocrine abnormalities) and Angelman syndrome (cortical atrophy, cerebellar dysmyelination, Purkinje cell loss) are imprinting disorders whose typical characteristics are influenced by whether the maternal or the paternal copy of the critical chromosomal region 15q11-13 was responsible.
A study was carried out on a group of discordant monozygotic twins in which their entire genome sequences, transcriptome and methylome were searched for tantalising allelic differences in the use of maternal compared to paternal copy that could potentially accord differing susceptibility to multiple sclerosis. A group of such differences were successfully identified. Preferential allelic expression, either due to imprinting, resistance to X inactivation, etc, is crucial to the pathogenesis of many neurologic and psychiatric disorders.
Transgenic mouse models
The development of transgenic mouse models for neurologic diseases has been pivotal in the advancement of Neurogenetics. The mouse model has been especially fruitful in the investigations of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. These models are beneficial in analysing pathogenesis of disease and establishing and testing novel therapies. Models in both Caenorhabditis elegans and Drosophila have also been exceedingly useful, peculiarly in studying genetic modifiers as well as therapeutic interventions.
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