Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-05-02
2003-12-09
Falk, Anne-Marie (Department: 1636)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023100
Reexamination Certificate
active
06660476
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to two single nucleotide polymorphisms, identified as A/G-182 and G/A-387, in the 5′ region of the human phenylethanolamine N-methyltransferase (PNMT) gene, the gene products thereof, and to methods for the determination (diagnosis) of susceptibility to (risk of) neurologic or neuropsychiatric diseases involving adrenergic neurons.
The publications and other materials used herein to illuminate the background of the invention or provide additional details respecting the practice, are incorporated by reference, and for convenience are respectively grouped in the appended Bibliography.
The noradrenergic neurons of the locus coeruleus (LC) innervate more brain areas than any other nucleus. This nucleus is involved in sleep, arousal, vigilance, attention, cognition, memory, learning, response to stress, brain activity, emotion and regulation of the autonomic nervous system (Aston-Jones et al., 1999); Aston-Jones et al., 1996). The major efferents that convey nerve impulses to the locus coeruleus derive from the epinephrine and phenylethanolamine N-methyltransferase (PNMT) rich neurons of the C1 (paragigantocellularis) and C2 (prepositus hypoglossi) nuclei of the rostral medulla oblongta (Aston-Jones, et al. (1996); Aston-Jones, et al. (1986)). These medullary centers in turn serve as the gateway between the central nervous system (CNS) and the autonomic functions of blood pressure, pulse, respiration, pain modulation, somatic sensations and skin conductance. Given this breadth of involvement, it is not surprising that defects in the noradrenergic-LC system have been implicated in a number of disorders including attention deficit disorder (Aston-Jones et al., 1999), post traumatic-stress disorder (Aston-Jones et al., 1994), depression (Siever and Davis, 1985), manic-depressive disorder (Bunney, 1977), anxiety (Aston-Jones et al., 1996), antisocial personality disorder, Alzheimer's disease (Chan-Palay, 1991) and Parkinson's disease (Chan-Palay, 1991).
The PNMT enzyme is primarily expressed in the adrenal medulla and the retina (Baetge et al., 1988). Its activity increases after stress in response to glococorticoids and neuronal stimulation (Betito et al., 1994). Since defects in epinephrine metabolism have been implicated in the etiology of attention deficit hyperactivity disorder (ADHD), aggression and anxiety (Girardi et al., 1995; Hanna et al., 1996; Klinteberg and Magnusson, 1989; Pliszka et al., 1994), PNMT is a candidate gene for a range of neurologic and neuropsychiatric disorders.
Alzheimer's Disease (AD), the most common type of dementia, is characterized by two hallmark abnormal protein deposits in the brain: beta amyloid (&bgr;A) plaques and the paired helical filaments (PHF), constituents of neurofibrillary tangles (NFT). Currently, there are three genes, and their diagnostic mutations, on chromosomes 21, 14, and 1 which have been shown to cause the early onset form of familial AD (EOAD). These three genes, the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), respectively, are responsible for the familial form of AD (FAD) where inheritance follows an autosomal-dominant fashion. Inheritance of a fourth gene, the apolipoprotein (APOE4) on chromosome 19, increases the risk of the sporadic form of late onset AD (LOAD). Additionally, loci found throughout the genome also have shown some evidence of association with the sporadic forms of LOAD (for a review see Price et al., 1998), and more recently with EOAD (Grimaldi et al., 2000). This provides strong evidence that AD is a polygenic disorder and ascribes to a multifactorial mode of inheritance in which the simultaneous action of multiple genes contributes to the disease phenotype. It is likely that not all of the genetic components of AD have been identified; therefore, further investigation is needed to elucidate additional genetic components.
Several reports have shown that selective neuronal loss in AD is a consequence of degeneration of specific neurotransmitter systems (Beal et al., 1986; Davies et al., 1980; Davies and Maloney, 1976; Perry et al., 1981; Yammamoto and Hirano, 1985), although the mechanism by which these deficits occur is for the most part unknown. One notable exception is found in a series of studies by Burke and colleagues (Burke et al., 1987) where they have shown that phenylethanolamine N-methyltransferase (PNMT) levels are decreased in the brains of persons with AD when compared to normal healthy control brains. PNMT, the rate-limiting enzyme in the catecholamine biosynthesis pathway (Axelrod et al., 1972) found on chromosome 17q21-q22 (Hoehe et al., 1992), is a specific marker for adrenergic neurons (Burke et al., 1990) because it mediates the conversion of norepinephrine (NE) to epinephrine (Epi). This suggests that PNMT is an important enzyme in the metabolism of both of these essential neurotransmitters and in AD.
Epi neurons are known to comprise approximately 85% of the C-1 neurons of the rostral ventral lateral medulla, a part of the caudal brain stem (Arango et al., 1988). Burke, et al. (1987) have demonstrated that adrenergic neurons of this region have afferent projection sites to the frontal cortex, amygdala, locus coeruleus and hippocampus. Collectively, these subcortical nuclei regulate attention, memory, emotion, and behavior. Notably, these brain regions and their associated functions are known to be affected in AD (Burke et al., 1988). Burke and colleagues found that AD patients displayed significant decreases in PNMT enzyme activity and it was determined that these decreases were due entirely to reductions in the amount of PNMT enzyme protein (Burke et al., 1988; Burke et al., 1987).
Epidemiological, twin and adoption studies have provided substantial evidence that Multiple Sclerosis (MS) has a strong genetic component (Ebers et al., 1986; Sadovnick et al., 1993; Mumford et al., 1994; Ebers et al., 1995). Research efforts have focused primarily on bi-allelic polymorphisms in candidate genes, which have been implicated in either the immune response or in myelin production (Dyment et al., 1997; Kalman and Lublin, 1999). In addition, three independent groups have performed genome screens (Ebers et al., 1996; Sawcer et al., 1996; Haines et al., 1996; Kuokkanen et al., 1997) in the hopes of elucidating novel chromosomal regions and potential candidate genes that may contribute to susceptibility to MS. Collectively, these studies provide evidence to suggest MS is a polygenic disease (Dyment et al., 1997; Bell and Lathrop, 1996), in which the additive effects of many susceptibility loci contribute to the disease phenotype.
The PNMT locus was identified in a genome screen by Swacer et al. (1996), and later by Kuokkanen, et al. (1997) to harbor a gene that may confer susceptibility to MS. In MS, the immune system mistakenly attacks self-molecules found within the brain and spinal cord (Steinman, 2000); cytokines are thought to play an intimate role in the progression of these biological effects on the CNS (Benveriste, 1995). Immune cells express various alpha-adrenergic and beta-adrenergic receptors that are sensitive to catecholamines, such as NE and EPI (Haskó and Szabó, 1998). The signaling mechanisms for the immune response are modulated by catecholaminergic input to both immune cells, which stimulate cytokine production, and adrenal cortical cells, which rely on the hypothlamo-pituitary-adrenal (HPA) stress axis to modulate glucocorticoid production (Vizi, 1998). Furthermore, modulation of immune/inflammatory mediators (like cytokines and chemokines) is dependent upon the activation of these adrenergic receptors (Haskó and Szabó, 1998) by catecholamines.
Adrenergic genes appear to play a role in bipolar disorder. Attention deficit hyperactivity disorder ADHD is a disorder of cognition and arousal (Weinberg and Harper, 1989; Mefford and Potter, 1989) and noradrenaline is closing linked to both (Aston-Jones et al., 1984; Carli et al., 1983; Usher et al., 1999). Aston-Jones et
Comings David E.
MacMurray James P.
City of Hope
Falk Anne-Marie
Qian Celine
Rothwell Figg Ernst & Manbeck p.c.
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