Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic L-amino acid decarboxylase

Abstract

Aromatic-L-amino-acid decarboxylase (AADC) is an enzyme that plays an essential role in synthesizing catecholamines and serotonin in neuronal and endocrine tissues. AADC has also been detected in other nonneuronal tissues including liver and kidney, although its physiological role in nonneuronal tissues has not yet been defined. Previously we have cloned a human AADC cDNA from a neuronal tissue (pheochromocytoma) [Ichinose, H., Kurosawa, Y., Titani, K., Fujita, K., & Nagatsu, T. (1989) Biochem. Biophys. Res. Commun. 164, 1024-1030] and the corresponding genomic DNA [Sumi-Ichinose, C., Ichinose, H., Takahashi, E., Hori, T., & Nagatsu, T. (1992) Biochemistry 31, 2229-2238]. Here we present isolation and characterization of AADC cDNA and genomic DNA from a nonneuronal tissue (human liver). The nonneuronal and neuronal AADC mRNAs differed only in the region corresponding to the untranslated first exon. The first exon for the nonneuronal-type mRNA was located 4.2 kilobases upstream to that for the neuronal-type mRNA and 22 kilobases from exon 2, to which it is spliced. Determination of the transcription initiation site indicated that the length of the nonneuronal-type exon 1 was 200 bp. A TATA box-like motif was located between positions -26 and -20 from the transcription initiation site. These results showed that an alternative usage of the first exon in the 5'-untranslated regions produces two types of mRNAs in AADC and suggested that alternative splicing would regulate the tissue-specific expression of AADC.

Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension

“…L-DOPS is decarboxylated to NE by the enzyme L-AADC, which is extensively expressed in neural and nonneural tissues (eg, stomach, liver, and kidney). 16 Because L-DOPS crosses the blood-brain barrier, 17 its pressor effect could be attributable to central activation of sympathetic outflow 18 ; however, the results of this study indicate a peripheral mechanism of action. Concomitant administration of L-DOPS with carbidopa, an inhibitor of L-AADC that does not cross the blood-brain barrier and thus inhibits NE synthesis only outside the central nervous system, blocked both the pressor effect and the increase in plasma NE.…”

“…Because patients with PAF have extensive loss of postganglionic sympathetic neurons, nonneural tissue, most likely stomach, liver, or kidney-where L-AADC is extensively expressed-may be the major site of NE generation from L-DOPS. 16 Although precursor therapy with L-DOPS effectively treats NOH, it is not yet known whether supplementation of the depleted neurotransmitter offers additional advantages over direct agonist therapy with agents such as midodrine or pseudoephedrine, which stimulate ␣-adrenoreceptors. The incidence of supine hypertension, a common adverse consequence of treatment of orthostatic hypotension, was similar with L-DOPS to that in previous trials using direct adrenergic agents to treat orthostatic hypotension.…”

Genomic Imprinting of Dopa decarboxylase in Heart and Reciprocal Allelic Expression with Neighboring Grb10

“…Human DDC is located on chromosome 7p12.2 in a region of conserved linkage with GRB10 and consists of 15 exons spanning 107 kb (64). Two DDC transcripts, a neuronal isoform and a nonneuronal (endoderm-specific) isoform, have been characterized in humans, and like mouse Ddc these differ only in having alternative 5Ј noncoding exons that initiate from distinct promoters (29,31,63). VISTA plot analysis between mouse and human Ddc/DDC genomic regions (Fig.…”

“…However, DDC is expressed not only in dopaminergic and serotonergic neurons of the central and peripheral nervous systems but also in several nonneuronal tissues, with high levels present in liver, pancreas, kidney, and intestine, thus setting it apart from other catecholamine pathway enzymes. Promoter switching and alternative splicing have been shown to direct tissue-specific DDC expression in neuronal and nonneuronal lineages (2,3,13,20,29,31,37).…”

Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma

“…The single-copy gene encoding DDC maps to chromosome 7p12.2, close to the epidermal growth factor receptor (EGFR) gene, and is composed of 15 exons spanning a genomic region of more than 85 kb (Ichinose et al, 1989;Sumi-Ichinose et al, 1992). Furthermore, two other DDC mRNA transcripts encoding distinct DDC protein isoforms as well as alternative splicing in 5 0 -untranslated region have been identified and characterised (Krieger et al, 1991;Ichinose et al, 1992;O'Malley et al, 1995;Vassilacopoulou et al, 2004).…”