Acromegaly is caused by excessive growth hormone production, most often due to pituitary adenomas. Characterized by acral growth, the disease manifests insidiously in adults and can be potentially life-threatening. In growing children, the disease presentation is dramatic with disproportionate linear growth leading to gigantism. Inaccessibility of the gland for biopsy, lack of functional cell lines and tumor heterogeneity has constrained the elucidation of molecular etiology of the disease. In collaboration with PGIMER, Chandigarh, we initiated whole-exome sequencing (WES) studies to identify genetic basis of acromegaly in Indian patients, which will aid in clinical assessment of pathogenecity. In familial cases, genetic studies are carried out and the clinician is informed of the risk factors to facilitate genetic counseling to the family.
Hearing impairment is one of the most frequent sensory defects and can be classified into congenital and acquired. Congenital hearing loss can be caused by hereditary and non-hereditary genetic factors. The identification of the causal hereditary mutation leading to congenital hearing impairment is important for early diagnosis, clinical follow-up and genetic counseling. India is a country with high ethnic diversity and high degree of consanguinity in some pockets. In collaboration with Command Hospital, Bangalore, we initiated a whole-exome sequencing project to identify causative novel variants/genes in this genetically heterogeneous recessive disease.
Genetic diagnosis of primary immune deficiency (PID) diseases in India is subject to numerous obstacles in terms of evaluation, characterization and turnaround time for definitive diagnosis and treatment. Few established centers in the country provide comprehensive genetic and prenatal diagnosis for primary immune deficiencies. Additionally, a diverse range of infections endemic to our country and nutritional deficiencies serve to further complicate PID diagnosis. Obtaining a specific molecular diagnosis has significant implications for patient management, including genetic counseling and providing prenatal diagnosis. Therefore, it becomes important to establish facilities for quicker diagnosis of the underlying genetic defect. Higher degree of consanguinity and ethnic diversity in India also necessitates the need for molecular confirmation of the genetic players suspected to be related to a particular PID case. In collaboration with National Institute of Immunohematology in Mumbai, we have now initiated studies to identify the variants/genes involved in disease pathogenecity.
Intellectual disability (ID) previously referred to as mental retardation (MR) is a neuro developmental disorder with significant limitations in intellectual functioning and adaptive behavior. XLID is a clinically and genetically heterogeneous disorder, and exists in both syndromic and non-syndromic forms. Family based association studies have identified more than 100 genes known to be implicated in XLID. However, the cause of the disease is still unknown for the non-syndromic form of XLID and is poorly studied. In collaboration with Dr. Girimaji from NIMHANS, we collected samples from more than 40 families with more than 80 individuals affected with moderate to severe ID. Due to genetic variability of XLID, cytogenetic tests followed by array comparative genomic hybridization were performed to investigate copy number alterations and larger chromosomal deletions/duplications in all the families. Whole-exome sequencing was initiated to identify novel variants/genes involved in intellectual disability.
Kinases and phosphatases
have an equal role to play in phosphorylation and dephosphorylation
of proteins that are responsible for transmitting signals
from an external stimulus to the final expression of required
functional genes through a cascade of signaling molecules. However,
actions of phosphatases are less investigated as opposed
to kinases. We are identifying substrates of protein tyrosine
phosphatases that are involved in human diseases in a global
scale using substrate trapping mutants of protein tyrosine
phosphatases in order to evaluate their functional aspects
that will result in the identification of lead molecules
for therapeutic interventions.
Esophageal cancer is the third leading cancer in males and fourth leading in females in India, but not much
is known about the molecular etiology of the disease. We have used DNA microarray technology for high throughput
identification of molecular gene expression profiles. We observed 881 genes significantly upregulated in ESCC
samples as compared to the adjacent normal epithelium. The expression of two previously unreported overexpressed
genes, ORAOV2 and FAP, was validated at the protein level by immunohistochemical labeling
of tissue microarrays and archival tissue sections. Overall, using this approach, we have identified a number of promising novel candidates that can be validated further for their potential to serve as biomarkers for ESCC. This is a collaborative effort between IOB, Kidwai Memorial Institute of Oncology and Johns Hopkins School of Medicine. Similarly, we are working on copy number variations in ESCC using arrayCGH.
Similar approaches are adopted for diverse cancers such as pancreatic cancer, gastric adenocarcinoma, gall bladder carcinoma, hepatocellular carcinoma, leukoplakia and oral squamous cell carcinoma, cervical cancer and retinoblastoma. Other diseases for which transcriptomic profiling are being done include temporal lobe epilepsy, tuberculous meningitis, rheumatoid arthritis, osteoarthritis, spondyloarthropathy and reactive arthritis. We also use this technology to identify subset of genes which are responsible for the development of skin lesions in arsenic exposed patients.