A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration.

Charcot–Marie–Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound heterozygous mutations in a gene that encodes ganglioside-induced differentiation-associated protein-1 (GDAP1). GDAP1 is located on 8q21, and plays a major role in ganglioside differentiation and Schwann cell function, as well as regulates neuronal and axonal development. In this study, we recruited a consanguineous south Indian family with an affected patient, an unaffected sibling, and the mother. The patient was affected with progressive weakness in the lower and upper limbs, atrophy of small muscles of the foot and hands, club shaped hands, steppage gait, hoarseness, and decreased muscle tone. His nerve biopsy examination revealed peripheral nerve demyelination and nerve conduction testing confirmed a reduction in nerve activities, while MRI showed mild degenerative changes in the cervical spine. Further, targeted exome sequencing (TES) and copy number variation analysis were performed on the patient. TES identified a compound heterozygous mutation that includes a missense mutation and a 3’UTR mutation (NM_018972.4: c.413A > G:p.His138Arg; g.74488790C > A:c.*29C > A, respectively) in GDAP1. The missense change is not reported in available public databases, while the UTR variant is seen only in the South Asian population in gnomAD (allele frequency = 0.00002). Multiple in silico prediction tools show that the missense mutation is damaging. Subsequently, in silico protein modeling, phylogenetic conservation analysis, and the impact of the mutation on the canonical transcript have also been performed. The compound heterozygous mutation was confirmed in the patient by PCR-Sanger sequencing and was shown to segregate within the family. The combined results support the fact that these two mutations in GDAP1 link the genotype–phenotype correlation in the family. This will help the family in genetic testing, counseling, and early diagnosis. Our findings support expanded phenotypic characterization along with the genetic spectrum of GDAP1 mutations in CMT type4A in the Indian population.

Within the ryanodine receptor family (RyR), three genes (RyR1, RyR2, and RyR3) are involved in Ca2+ homeostasis, storage, and regulation. Mutations in RyR1 causes a wide range of clinical phenotypes, including several congenital myopathies (CM), central core disease (CCD), and hyperthermia susceptibility. RyR1-related CCDs usually show clinical heterogeneity and an early onset of disease pathogenesis. Here, we present a family that includes unaffected parents and three siblings who have been affected with muscle problems since childhood. The clinical features include lower proximal muscle weakness, difficulties in standing up and climbing, skeletal malformations and hypotonia. Clinical examinations (e.g., nerve conduction velocity, electromyography, and muscle magnetic resonance imaging) showed weak muscle intensity, activity, and muscle atrophy. Whole-exome sequencing was performed in two affected siblings along with unaffected mother in the family using Illumina NovaSeq2500. Bioinformatic analysis and filtering of multiple variants revealed a novel variant in RyR1. This compound heterozygous variant (c.A5096G: p.D1699G+c.C5097AA: pD1699E; 13423_13424del:p.K4475Efs*106) has not been reported in public databases and in silico analysis predicted that the variant is damaging. Furthermore, this novel variant segregates within the family and in silico protein analysis showed putative changes in the protein activity between the wildtype versus mutant RyR1. The initial functional analysis showed changes in calcium channel activity, however, additional confirmational assays are required. Our study explains a genotype-phenotype correlation in the family. It expands the requisite prenatal diagnosis in the family and in the near future will provide a platform for therapeutics in RyR1-related diseases.

X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.

Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson’s disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case–control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373 T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808 T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson’s disease progression, and to enhance diagnostic capabilities.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10–15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digenetic/polygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimer’s disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype–phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.

Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T>C) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.

Pathogenic variants in the Oligophrenin 1 gene (OPHN1) cause an X-linked intellectual disability syndrome with a phenotype typically consisting of cerebellar hypoplasia, ventriculomegaly, seizures, facial dysmorphism, speech delay, and sometimes behavioral difficulties. OPHN1 is located in Xq12 and encodes a Rho-GTPase activating protein that regulates various cellular processes such as endocytosis, dendritic growth, morphology, synaptic localization, plasticity, and function. This study describes a male patient with global developmental delay, cerebellar hypoplasia, and other neuroanatomical findings suggestive of a Dandy-Walker malformation. A clinical pontocerebellar hypoplasia panel revealed a partial duplication from exon 7 to exon 15 in OPHN1 which was maternally inherited. PCR-Sanger sequencing of cDNA showed a truncating frameshift in the OPHN1 transcript. Further, transcript level analysis of OPHN1 showed a 75% reduction in the total expression in the patient in comparison to controls. Presumably, this leads to a similar decrease in the level of OPHN1 protein resulting in the observed phenotype. This is the first report of a partial duplication of exons 7-15 in OPHN1 in a patient with strabismus, speech delay, dysmorphic facial features, epilepsy, an autism-like phenotype, and developmental delay.

Many proactive steps have been taken worldwide to fight against the SARS-CoV-2 pandemic and to prevent COVID-19 spread with realistic approaches. Recently, a novel variant B.1.617.2 has been identified in India, which is rapidly transmitting to other countries, challenging current therapeutics, wide vaccination and future research in COIVD-19.

DPP6 encodes a transmembrane protein that expresses highly in the hippocampal regions of the brain and regulates dendritic excitability. Recently, rare and loss of function variants were reported in DPP6 and further demonstrated to be associated with early onset Alzheimer Disease (AD) and frontotemporal dementia. We performed single variant and gene-based analyses in three non-Hispanic white cohorts: a familial late onset AD (cases=1212, controls=341), an unrelated early onset AD (cases=1385, controls=3864) and in the unrelated Alzheimer disease sequencing project (ADSP, cases=5679, controls=4601). Neither single variant or gene-based analysis revealed any significant statistical association of DPP6 variants with the risk for AD in the cohorts examined.

Greenwood Genetic Center, Greenwood, South Carolina, Department of Pediatrics, Department of Ophthalmology, Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA, Unité de Glycobiologie Structurale et Fonctionnelle, UMR 8576 CNRS, Université de Lille, Villeneuve d’Ascq, France and Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Intellectual disability (ID) is characterized by limited intellectual functioning and adaptive behavior, with a global prevalence of similar to 1-2%. Around 50% of ID cases have a genetic basis, with chromosomal and single gene mutations accounting for similar to 17-19% and rare de novo copy number variations (CNVs) for similar to 15% of the total cases. Thus, similar to 30-50% of the cases still remain unexplained. We investigated a north-eastern Indian family with two male children affected with mild syndromic ID. Both the affected siblings were first screened for mutations in genes implicated with syndromic ID on clinical suspicion (NHS and OCRL) in this family and found to be negative. Further, CNV analysis was carried out in the family using HumanCytoSNP-12 oligonucleotide array. Analysis revealed a 9.8 Mb de novo heterozygous deletion at 13q14.2-q21.1 that was shared among the affected siblings but not with their unaffected brother and parents. The deletion was confirmed by using quantitative-PCR which revealed a significant loss in copy number in both the affected siblings. This region encompasses genes functionally relevant to the ID phenotype, such as CKAP2, SUGT1, LECT1, DCLK1and SMAD9. A range of deletions spanning 13q13.3-13qter with variable phenotypes and haploinsufficiency have been reported in literature, but a de novo heterozygous deletion shared among siblings as seen in this study is very rare. Though the mechanism underlying this deletion remains unknown, our finding reiterates the notable contribution of this chromosomal region to ID, warranting more such studies to identify genetic underpinnings underlying ID. Such discoveries would lead to more personalized treatment regimens for ID individuals.

Background: A novel homozygous missense mutation (c.773G > A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified.Methods: An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family.Results: We identified a novel homozygous mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silica tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity.Conclusions: We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities. (C) 2016 Elsevier Ltd. All rights reserved.