Journal of Multiple Sclerosis
ISSN - 2376-0389NLM - 101654564
Mini Review - (2024) Volume 11, Issue 3
There is little room for doubt regarding the transformative impact of genetics on our comprehension of the mechanisms underlying brain disorders. In the past twenty years, there has been remarkable advancement in achieving precise molecular diagnoses and expanding our knowledge about the genes and pathways implicated in numerous neurological and psychiatric conditions. Similarly, novel techniques and analytical methodologies, such as genome array studies and "next-generation" sequencing technologies, are providing deeper insights into the intricate genetic framework that dictates our susceptibility to these disorders. As we endeavor to translate these revelations into clinical applications, a significant hurdle facing the field is the need to bridge the gap between genetic discoveries and their biological implications. In this overview of Neuron's special review edition on neurogenetics, we reflect upon the progress achieved during the preceding two decades and underscore the challenges and promising prospects that lie ahead.
Multiple sclerosis • Neurogenic Diseases • Psychiatric
The initial rendition of the human genome sequence marks a significant milestone, and as frequently observed with such anniversaries, there has been extensive recent discourse, both in the scientific realm and among the general public, concerning what is often referred to as 'the genetics revolution' and its influence on the fields of science and medicine. In this essay, we aim to delineate the achievements and obstacles associated with research focused on neurogenetic diseases. As we contemplate the progress made in neurogenetics over the past two decades, there has been a profusion of remarkable revelations. Yet, there are also opportunities to glean valuable insights from unsuccessful experiments and an occasion to ruminate on the challenges that may have hindered or postponed the development of effective interventions for certain disorders.
Undoubtedly, the sequencing of the human genome stands as a pivotal scientific achievement that has fundamentally transformed the fields of biology and medicine. However, it's worth noting that the decade preceding the culmination of the human genome project already witnessed a burgeoning interest in neurogenic. In hindsight, it becomes evident that numerous captivating breakthroughs would have remained unattainable without pivotal collaborations between perceptive clinicians and technically innovative basic scientists. Equally astonishing is the extent to which these genetic revelations have enriched our understanding, not only of specific diseases but also of fundamental neurobiology.
The identification of the Duchenne Muscular Dystrophy (DMD) gene in the years 1986-1987 serves as a striking example of the indispensable role played by clinical genetics, cytogenetics, and linkage analysis in pinpointing the precise gene location [1-4]. DMD constituted one of the initial genetic discoveries related to an inherited disorder, and over the past two decades, it has emerged as a paradigmatic disorder for pioneering the development of novel diagnostics and therapeutics for genetic conditions.
In 1983, a significant breakthrough occurred with the mapping of the Huntington Disease (HD) gene to the short arm of chromosome 4. This achievement was made possible through the use of restriction fragment length polymorphisms and linkage analysis in a large family, ushering in a new era where disease genes could be mapped without prior knowledge of cytogenetic abnormalities [5]. Similarly, the identification of dinucleotide polymorphic repeats and the convenience of genotyping such repeat using Polymerase Chain Reaction (PCR) greatly facilitated genetic mapping [6]. This was instrumental in uncovering duplications and deletions of the PMP22 locus as the causative factors behind Charcot-MarieTooth Disease (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively [7, 8]. These pivotal discoveries marked the beginning of exploring genomic disorders in neurobiology and beyond [9]. Similar amalgamations of advanced cytogenetics, somatic hybrid techniques, and molecular genotyping played a vital role in refining the maps of various neurodevelopmental disorders, including fragile X syndrome, Miller-Dieker lissencephaly, and Prader-Willi syndrome [10-13]. The discovery of polymorphic trinucleotide and tetranucleotide repeats represented a crucial advancement in elucidating dynamic mutations as a novel mutational mechanism in several neurological disorders [14]. This discovery helped resolve clinical mysteries such as the Sherman paradox in fragile X-syndrome and the phenomenon of anticipation, involving earlier and more severe disease onset in successive generations, as observed in disorders like myotonic dystrophy, HD, and the ataxias.
The development of large insert cloning and other physical mapping techniques as integral components of the framework for sequencing the human genome, played a pivotal role in facilitating the discovery of numerous disease genes in the 1990s [10, 11]. Indeed, the cloning of the Rett syndrome gene in 1999 would not have been achievable without the intensive mapping and sequencing efforts dedicated to the X chromosome [15].
In exploring our own human genetic makeup, we have gained valuable insights into shared biological aspects with other species. Take, for instance, the FOXP2 gene, which was identified in a family exhibiting developmental verbal dyspraxia-a condition characterized by difficulties in sequencing muscle movements needed for speech [14]. While this condition has a clearly defined phenotype in humans, it is so subtle that it would go unnoticed in another species. However, recognizing this phenotype in humans has enabled the demonstration that the FOXP2 transcription factor plays a vital role in neuronal circuitry in mice and songbirds [15,16].
In the realm of genetics, we have encountered situations where different genes can produce a seemingly identical phenotype, and conversely, one gene can give rise to multiple phenotypes. The improved diagnostic tools and increased clinical scrutiny over the past century have allowed us to comprehensively document the clinical and pathological aspects of various disorders, leading to their classification into distinct categories. While these clinical classifications have been essential in understanding disorders with overlapping phenotypes, they also have limitations. They tend to change periodically based on evaluations by experts, enhanced documentation of signs and symptoms, and the availability of new diagnostic tests, making it challenging to keep up with evolving classifications. Additionally, discrepancies between clinical criteria and pathological findings can sometimes blur the lines between categories.
Genetics is now starting to address these challenges, shedding light on the perplexities of classifications and categories. Many inherited ataxias, for example, share clinical similarities but are found to result from mutations in different genes. Similarly, various neuropathies, dystonias, myopathies, and cognitive disorders exhibit clinically indistinguishable characteristics yet have distinct genetic underpinnings. In instances where clinical overlap exists but different genes are involved, this similarity often reflects convergent biology and shared pathways. Extensive research has shown that the proteins produced by many of these genes, which causes overlapping phenotypes, interact either directly or indirectly and often function within intersecting pathways. This phenomenon is observed in disorders such as ataxias, muscular dystrophy, tuberous sclerosis, autism spectrum disorders, Parkinson's disease, and Alzheimer's disease.
Ultimately, the discovery of the causative genes for these disorders may render clinical classifications obsolete, as future generations of neurologists could potentially rely on the underlying DNA mutation to categorize a disorder. Moreover, from a basic science perspective, with the extensive documentation of human phenotypes and the rapidly expanding knowledge of causative genes, reevaluating clinical data and considering the implications of distinct genetic causes may lead to new hypotheses about functionally related pathways. This approach mirrors the way Drosophila geneticists have elucidated the Notch signaling pathway by starting with mutants that share similar phenotypes.
Indeed, a critical lesson emerges from our exploration of the brain—the brain represents a vast landscape of potential mutations, with many genetic loci encoding proteins that interact intricately. Disruption of any one of these loci may yield consequences similar to the malfunction of an entire pathway. In light of this complexity, it's not surprising that only a handful of robust genome-wide association signals have been revealed for psychiatric disorders. When we group various phenotypes into a single clinical category, such as schizophrenia, the substantial genetic heterogeneity within the group severely limits the statistical power of association studies. Therefore, it may be prudent to consider categorizing behavioral phenotypes into highly specific subcategories, similar to the approach taken for the diverse genetic ataxias, when embarking on gene identification efforts.
An intriguing discovery is that mutations in a single gene can produce distinct clinical phenotypes in different patients. For example, consider the Aristaless-Related Homeobox Gene (ARX), which can lead to X-linked lissencephaly, agenesis of the corpus callosum with abnormal genitalia, cognitive deficits with or without seizures, or cognitive deficits accompanied by dystonia and seizures (Partington syndrome) [16, 17]. Similarly, the SHANK3 gene exhibits mutations that can result in Phelan McDermid syndrome, Asperger syndrome, autism, and even rare cases of schizophrenia. Likewise, mutations in NRXN1 can cause rare forms of both autism and schizophrenia, while mutations in LMNA, responsible for encoding lamin A and lamin C, can manifest as diverse disorders, including Emery-Dreifuss muscular dystrophy Type 2, Charcot-Marie-Tooth Axonal Neuropathy (CMT2B1), limbgirdle muscular dystrophy Type 1B, Hutchinson-Gilford progeria syndrome, and various other distinct clinical phenotypes [14-18].
Taken together, these findings suggest that the neuroanatomical and physiological disturbances resulting from the dysfunction of these genes may be influenced by the unique genetic backgrounds and environmental experiences of affected individuals, thereby leading to different clinical outcomes in various patients.
In line with these observations, some of the most intriguing revelations in neuroscience concern the exquisite sensitivity of the nervous system to the dosage of numerous proteins. It appears that both Haploinsufficiency (a condition where one functional copy of a gene is insufficient) and gene duplications can lead to overlapping neurological phenotypes. This phenomenon is observed in various conditions, including Parkinson's disease, Alzheimer's disease, peripheral myelin protein 22 in neuropathies, MeCP2 in Rett syndrome, MeCP2 duplication disorders, as well as gain-of-function and loss-offunction mutations in neuronal ion channels that contribute to epilepsy and other neurological deficits.
While the precise mechanisms underlying how both the loss and gain of the same proteins result in similar cognitive and social behavior phenotypes remain elusive, it is conceivable that these phenotypes manifest as a consequence of disrupted neuronal homeostatic responses due to downstream effects of various molecular changes. Understanding these neuronal homeostatic responses and their potential modulation could hold the key to the development of therapeutic interventions for a wide range of disorders, regardless of the specific primary genetic defect at play.
Citation: Diaz.T, Hart. M and Joy. E. Advancing Neurogenetics: Pioneering the Future of Brain Research. J Mult Scler 2024, 13(3).541
Received: 10-Mar-2024, Manuscript No. JMSO-23-114570; Editor assigned: 12-Mar-2024, Pre QC No. JMSO-23-114570; Reviewed: 20-Mar-2024, QC No. JMSO-23-114570; Revised: 22-Mar-2024, Manuscript No. JMSO-23-114570; Published: 30-Mar-2024
Copyright: ©2024 Diaz T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
