Variants, transcript diversity and microbial diversity in COVID-19
Some of the factors that affect COVID-19 disease severity are the strain of SARS-CoV2, the host response and the existing microbial diversity of the host. In a series of studies published from Rajesh Pandey’s lab all these three factors have been studied in detail.
In the first study, it was shown that some of the mutations in S2 protein (subunit of spike protein) were retained in omicron sub variants as they increased the immune evasion by reducing the neutralization of S1 subunit by antibodies.
In the second study, they studied the diversity of transcripts along with gene expression in cases of COVID-19 patients that developed Acute Respiratory Distress Syndrome (ARSD). They found that the diversity of transcripts was reduced in case of severe ARSD and the existing transcripts promoted a proinflammatory state.
In the third study, they studied the existing microbial diversity, especially intracellular pathogens, in COVID-19 patients. They found differences in the microbial population of COVID-19 patients when compared with healthy individuals. Healthy individuals had more of commensal species as compared to COVID-19 patients which had pathogenic strains like Staphylococcus aureus, Mycoplasma mycoides, Leptospira interrogans.
Presence of bacteria like Buchnera aphidicola, Streptomyces clavuligerus, and Ehrlichia canis in B-cells, T regulatory cells was an interesting finding that needs further investigation.
Suppressed transcript diversity and immune response in COVID-19 ICU patients: a longitudinal study
Novel mutation in myoclonus-dystonia
Myoclonus-dystonia (MD) is a movement disorder which is characterized by muscle twitches (myoclonus) and involuntary muscle movements (dystonia). 30 – 50% of cases are because of mutations in SCGE gene (expressed in neurons and muscles but function is unknown). The cause for the rest of the cases of myoclonus-dystonia (MD) is unknown.
Mohd. Faruq’s lab reports an Indian patient with the disease who has a novel mutation in potassium channel tetramerization domain-containing protein 17 (KCTD17) gene. He is the first Asian patient to be reported with a mutation in KCTD17 gene. Only 11 MD patients with mutations in KCTD17 gene have been reported previously. In the current study, the effect of the particular variant present in the Indian patient was evaluated using the patient derived lymphoblastoid cell line. Calcium homeostasis, mitochondrial dysfunction and ER stress were observed in this cell line. The mechanistic cause of MD because of mutations in KCTD17 still needs to be further evaluated. The identification of the mutation has implications in choosing the treatment. In MD with mutations in KCTD17, deep brain stimulation of the globus pallidus interna has been reported to help the patients.
Childhood onset myoclonus-dystonia associated with a novel KCTD17 variant in an Indian patient
RFC1 repeat expansion and ataxia
Many of the neurodegenerative diseases, like spinocerebellar ataxia are inherited. Short tandem repeat expansions have been shown to be responsible for many of these diseases. We still don’t know the genetic cause for 60 – 70% SCA cases.
A new repeat – (AAGGG)400-2000 in the intron of RFC1 gene, replication factor complex subunit 1 that is essential for DNA repair, has been identified and found to be implicated in cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), ataxia and Parkinson’s disease. AAGGG repeat expansion in patients has been identified majorly in Europe. 90-100% cases of CANVAS are caused by this repeat expansion and 20-30% of other types of ataxia and neuropathy diseases. Studying the prevalence of AAGGG repeat expansion in the Indian population would provide better screening methods for ataxia in Indian patients.
In the present study, Mohd. Faruq’s lab studied three different disease cohorts – uncharacterized ataxia, spinocerebellar ataxia 12 (SCA12) and Charcot-Marie-Tooth (CMT) disease and a set of healthy controls to find the frequency of AAGGG repeat expansion. The healthy controls were taken from the IndiGEN study – that sequenced 1029 healthy Indian genomes. The frequency for biallelic (AAGGG)exp in SCA12 and CMt were found to be 1.5% and 2.5% respectively.
In addition to (AAGGG) expansion, they also found novel (AAAGG)exp /(AAGGG)exp mutations and other repeat sequences -AAAAG, AAAGG, AAAGGG, AAAAGG, AAGAG, AACGG in the ataxia cases studied. Further study will help in understanding how the repeat sequence and number of repeats are affecting the ataxia disease progression.
Gene variants in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) which leads to fibrosis and eventual lung scarring has been reported to have a genetic basis. In this study by Ritutshree Kukreti’s lab, literature mining and further analysis for identification of gene variants were performed. Four different variants, in genes responsible for mucin production, immune response and inflammation, host defense, cell–cell adhesion and telomere maintenance, showed maximum association with IPF disease susceptibility. Further studies are needed to understand the mechanism and the implication of these variants.