Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-07-23
2001-05-01
Jones, W. Gary (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100
Reexamination Certificate
active
06225057
ABSTRACT:
FIELD OF THE INVENTION
Panic disorder, agoraphobia, social phobia and other anxiety disorders affect 5-10% of the general population. There are no biochemical, cytological or molecular tools for the diagnosis of anxiety disorders. Moreover, the gene or genes predisposing to anxiety disorders have not yet been localised. We have studied the clinical association between panic/agoraphobia and joint hypermobility syndrome, and have identified several pedigrees in which these disorders cosegregate. We have detected a 10 centiMorgan (cM) duplication of human chromosome 15 (15q24-25) in the affected subjects of families with several members suffering from anxiety and depression disorders. The 15q24-25 duplication segregates with panic disorder, agoraphobia, social phobia, depression and joint hypermobility syndrome. The 15q24-25 duplication is strongly linked to panic disorder, agoraphobia, social phobia and joint hypermobility syndrome (lod score 4.9). Affected-only analysis for the phenotype defined only by the anxiety disorders gave a lod score of 3.36. All but one of the 45 subjects of these families with these anxiety disorders had the 15q24-25 duplication. Mosaicism was detected in 80% of the affected subjects, with 40-70% of their lymphocytes having the 15q24-25 duplication. We have also studied 50 unrelated non-familial cases of panic disorder and/or agoraphobia and all had the 15q24-25 duplication. The duplicated region contains 10 known genes of which NTRK3 and LOXL1 are likely to be involved in anxiety and joint hypermobility. We propose that this genomic mutation, which is present in 7% of the general population, is the major susceptibility mutation for panic disorder, agoraphobia, major depression and social phobia in familial and sporadic cases. We have developed cytological, cytogenetic and molecular methods for the specific diagnosis of the 15q24-25 duplication causing anxiety disorders.
PRIOR ART
Anxiety disorders are neurotic alterations that include generalised anxiety disorder, phobic disorders, panic disorders (panic attacks, panic disorder and agoraphobia) and obsessive-compulsive disorders. The prevalence of this group of alterations is estimated in about 10% in the adult population and up to 5% in infantile patients. Several million people worldwide are affected by anxiety disorders, but the actual prevalence rates of these alterations are probably higher.
Anxiety and panic disorders aggregate in families. The familial transmission of anxiety disorders has often been explained by common familial environmental factors. Twin studies of anxiety disorders have shown a high concordance among monozygotic twins. The mode of familial transmission of panic disorder is unclear, but it has been suggested that anxiety, panic attacks and agoraphobia have an autosomal dominant pattern of inheritance with incomplete penetrance. Although a major gene is supposed to be involved in panic disorder, multifactorial/polygenic inheritance has also been postulated.
The search for the gene(s) involved in anxiety disorders has been focused in the study of candidate genes and wide genome analyses. So far, only a moderate association with a polymorphism of the serotonin transporter (5-HTT) gene has been found, and is estimate to account for 3-4% of the total genetic variation in anxiety
1
. The failure to detect linkage for panic disorder, after the analysis of a large number of families and markers under different models of inheritance with various degrees of penetrance and in spite of high informativity has been attributed to locus heterogeneity and complexity of the phenotypes.
A strong association between anxiety disorders and joint hypermobility has also been reported
0
. The link between joint hypermobility and anxiety disorders has been further been clarified by the identification of features of anxiety in about 70% of patients with joint hypermobility
3
. Joint hypermobility is about 17 times higher in patients with panic disorders than in control subjects. The investigation of these associations may lead to the identification of susceptibility mutations for anxiety disorders. We have identified and interstitial duplication of chromosome 15q24-25 in the patients affected by panic disorder, agoraphobia, social phobia, major depression and joint hypermobility of these families, and also in unrelated non-familial cases of panic disorder and agoraphobia. The 15q24-25 mutation is the major genetic alteration of susceptibility for these anxiety disorders.
NTRK3 as a candidate for anxiety disorders
Among the few known genes in the 15q24-25 duplicated region the best candidate for anxiety disorders is the gene that encodes the neurotrophin-3 receptor, NTRK3, (also known as TRKC)
6,7
. Although neurotrophic factors have potential importance in neurodegenerative diseases, they have other roles and it has been suggested that they participate in psychiatric disorders. Thus, neurotrophic factors are involved in plasticity of the nervous system and may mediate the changes in neural connections associated with learning and memory. Moreover, it has been observed that anti-depressant drugs cause modifications of the levels of expression of neurotrophins and their receptors, in particular neurotrophin-3 (NT-3).
Within the human adult CNS, NTRK3 is abundantly expressed in the noradrenergic neurons of the forebrain, including the cerebral cortex, hippocampus, thalamus and hypothalamus, and is the only neurotrophin receptor detected in the locus coeruleus (LC). The LC is the principal norepinephrine (NE) containing nucleus in the CNS, playing a major role in behavioural arousal in response to novel or stressful stimuli. A significant increase in central noradrenergic function is relevant for the pathogenesis of panic disorder because the NE system integrates and coordinates fear responses to threatening stimuli. The specific expression of NTRK3 in noradrenergic neurons and its location in the duplicated chromosomal region in patients with panic disorders, which might cause its over-expression, argues for NTRK3 as an excellent candidate for anxiety disorders. Thus, the over-expression of NTRK3 in the LC might induce an excessive trophic and proliferative effect on NE neurones. Indeed, stress and antidepressants regulate NT-3 expression in the LC. Since the major source of NE in the forebrain is the LC, the final consequence of the over-expression of NTRK3 would be an over-activity and enhanced efficacy of the NE synapses, resulting in a dysregulation of the NE response. This would decrease the emotional arousal threshold of the individual and alter the alarm/fear regulatory system.
We have clearly demonstrated by linkage and affected-only analyses that a chromosome 15q24-25 duplication is involved in familial cases of several anxiety disorders, confirming the heritable condition of these alterations and defining a common biological background for panic disorder, agoraphobia and social phobia. The fact that the duplication has also been detected in all the subjects of an independent sample of unrelated patients affected by panic disorder and/or agoraphobia, arises the view that this chromosomal alteration is the major susceptibility mutation for these anxiety phenotypes. Although the psychiatric-clinical spectrum of the dup15q24-25 mutation is still not completely defined, we have shown the co-occurrence of this mutation in several psychiatric clinical groups, panic with or without agoraphobia, social phobia and simple phobia. From this study, it is clear that a pure entity including panic and agoraphobia can not be maintained and that a panic-agoraphobic spectrum model or a general neurotic syndrome seems more realistic from the genetics point of view. The 15q24-25 duplicated region may contain more than 50 genes, of which only 10 have been precisely mapped. We have developed cytological, cytogenetic and molecular methods for the diagnosis of the 15q24-25 duplication. At present, NTRK3 and LOXL1 are good candidates to explain the anxiety disorders presented here and joint hypermobility syndrome. The
Estivill Palleja Xavier
Gratacos Monica
Nadal Marga
Pujana Miguel Angel
Volpini Victor
Jones W. Gary
Ladas & Parry
Palleja, Zavier Estivell
Souaya Jehanne
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