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Genetic and Molecular Basis of Albinism in Indian Patients

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Genetic and Molecular Basis of Albinism in Indian Patients
Creator Sengupta, Mainak
Subject Molecular & Human Genetics
Description Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders characterized by the congenital hypopigmentation of ocular and cutaneous tissues associated with some developmental abnormalities of the eye. Mutations in genes that directly or indirectly regulate the multistep process of melanin biosynthesis are the basis of this disease. OCA is reported as one of the four major causes of childhood blindness in India; carrier detection followed by genetic counseling is the only way to contain the disease. The study presented in this dissertation is mainly focused on the understanding of the molecular pathogenesis of OCA in Indian patients recruited mainly from eastern and southern regions of India. The tyrosinase gene (TYR) encodes the rate-limiting enzyme of the melanin biosynthetic pathway, and on mutation causes OCA type 1 (OCA1). For my dissertation, I used TYR as the first candidate gene to study OCA. In an attempt to investigate the genetic lesions leading to OCA in the Indian population, 36 unrelated OCA pedigrees and 4 sporadic patients were subjected to cosegregation analysis and mutation screening. The mutation screening results of TYR suggested that the gene contributes to causation of the disease in 47.5% (19/40) of the OCA1 cases. Prevalence of defects in this gene in Indian population is primarily due to founder mutations and about 70% of the unaffected sibs of the OCA1 affected families were found to be carriers for TYR mutations. Among the nucleotide variants, unlike in/del and nonsense mutations, nonsynonymous (i.e. missense) changes could exert a very wide range of its effect on the translated protein – that is, from being significantly damaging to completely innocuous towards biological activity. Therefore, to evaluate functional implication of the missense variants by functional assays I selected the following variants: (a) six missense changes that we found in Indian OCA1 patients, (b) three other reported missense mutations, and (c) two reported cSNPs. Eight of the nine missense mutations were observed to lack both tyrosine hydroxylase and DOPA-oxidase activities; and one variant (R299S) retained minimal (14.61) tyrosine hydroxylase activity with respect to the WT protein. One of the cSNPs (I222T) was also found to be devoid of any enzymatic activity while the other (S192Y) was found to code for a hypomorphic variant. All of the variants excepting S192Y were subsequently found to be retained in the Endoplasmic reticulum. We also studied the role of other classical OCA genes viz. OCA2 (causal for OCA type 2), SLC45A2 (causal for OCA type 4) and TYRP1 (causes OCA type 3) as well as SLC24A5, a gene newly implicated towards melanin deficiency, in the tyrosinase positive OCA patients – that is where we could not find TYR mutations. Cosegreggation analysis followed by mutation screening revealed the following contribution of these four genes in causation of OCA: OCA2 – 12.5%, SLC45A2 – 7.5%, TYRP1 – 0% and SLC24A5 – 0%. We also studied single nucleotide polymorphisms (SNPs) in TYR, OCA2 and SLC45A2 in a large number of Indians belonging to various ethnic groups from across entire nation through a collaborative effort with Indian Genome Variation Consortium. The data can be used to evaluate utility of these variants as markers for these loci and future study on relative contribution of these genes in skin color variation in different population groups.
Date 2009-08
Type Thesis
Format application/pdf
Identifier http://www.eprints.iicb.res.in/527/1/Copy_of_Thesis_full.pdf
Sengupta, Mainak (2009) Genetic and Molecular Basis of Albinism in Indian Patients. PhD thesis, Jadavpur University.
Relation http://www.eprints.iicb.res.in/527/