IDDM2 and the Polymorphism of the Human Tyrosine Hydroxylase

Posted by James

INTRODUCTION

Polymorphisms in the tyrosine hydroxylase-insulin-insulin like growth factor 2 gene-regions (TH-INS-IGF2) on chromosome 11 were shown to have an association with type-1 diabetes. It is not yet clear whether TH gene carries susceptibility for type-1 diabetes. In the human, hTH molecules are encoded by at least three distinct messenger RNAs. The expression of these mRNAs varies in different parts of the nervous system. The calculated relative molecular mass of the deduced protein sequence is 55,473. Tyrosine hydroxylase is the first enzyme in the pathway of catecholamine synthesis. It catalyzes the formation of 3,4-dihydrox-yphenylalanine (DOPA) from tyrosine. hTH plays a central role in the neuronal transmission and hormonal action of catecholamines. Expression of the hTH gene is regulated in a tissue-specific fashionand is modulated by a variety of factors, such as cyclic AMP, glucorticoids, and trans-synaptic stimuli. The pathogenesis of some disorders of cate-cholaminergic neurons, such as schizophrenia, may be related to changes in hTH. The role of hTH in the pathogenesis of type-1 diabetes is not known, but many investigators are examining target organs, such as islet cell nerve and retina, for possible functional roles of hTH polymorphism. The hTH gene is located on chromosome llpl5.5 is composed of 14 exons interrupted by 13 introns, and spans ~8.5 kb.

The nucleotide sequence was determined for all 14 exons and their surrounding regions. Previous studies have investigated the association of type-1 diabetes and the hTH gene in Caucasians. It is not clear if there is any association between hTH polymorphism and type-1 diabetes.

Figure 1. Insulin Gene Region: Exon/lntron Organization of the Human TH Gene and TCAT Microsatellite Repeats Location

In the present study, we investigate the polymorphic microsatellite repeat (TCAT)n (Figure 1). Micro-satellite repeats have been suggested to have a function in recombination, in the generation of nucleosome positioning signals and in transcription. Microsatellites may also have effects in gene expression. Meloni et al. has demonstrated that the tetranu-cleotide repeat hTH microsatellite acts as a transcriptional enhancer in vitro. It was postulated that because of the transcriptional regulatory effect, hTH microsatellite could exert some activity on the expression of nearby genes, such as the drug insulin gene. This polymorphism begins at base pair 1,170 in intron 1 of the hTH gene. The following five alleles were previously reported by Polymeropoulos: Kl, K2, КЗ, K4, and K5. The length of these repeats is 260 bp, 256 bp, 252 bp, 248 bp, and 244 bp, respectively.
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