Polymorphism in tryptophan hydroxylase-2 controls brain serotonin synthesis

Abstract

A method of screening a subject for a serotonergic neurotransmission dysregulation disorder comprises detecting the presence or absence of an Tph2 mutation in the subject; and then determining that the subject is at increased risk of a serotonergic neurotransmission dysregulation disorder due to the presence or absence of the Tph2 mutation.

1 . A method of screening a subject for a serotonergic neurotransmission dysregulation disorder, comprising:
 detecting the presence or absence of an Tph2 mutation in said subject; and then   determining that said subject is at increased risk of a serotonergic neurotransmission dysregulation disorder due to the presence or absence of said Tph2 mutation.   
     
     
         2 . The method of  claim 1 , wherein said disorder is depressive disorder. 
     
     
         3 . The method of  claim 1 , wherein said disorder is anxiety disorder. 
     
     
         4 . The method of  claim 1 , wherein said disorder is obsessive compulsive disorder. 
     
     
         5 . The method of  claim 1 , wherein said detecting step includes a nucleic acid amplification step. 
     
     
         6 . The method of  claim 1 , wherein said detecting step includes an oligonucleotide probe hybridization step. 
     
     
         7 . The method of  claim 1 , wherein said Tph2 is human Tph2 and said mutation encodes a change in an amino acid of the encoded protein, said amino acid selected from the group consisting of A65, V66, F68, L77, F84, I94, R97, E105, P152, W153, P155, D162, L175, R191, E211, V223, P244, G251, R276, P277, V278, R285, R294, P308, Y310, E313, A333, I339, A342, S343, L344, A346, K353, V421, E423, A428, A436, R441, Y446, P449, Y450, and Q468. 
     
     
         8 . The method of  claim 1 , wherein said Tph2 mutation is selected from the group consisting of the human P449R mutation, the human R441H mutation, the human W153R mutation, the human A65V mutation, the human V66I mutation, the human L175V mutation, and the human Q468X (where X is a stop codon) mutation. 
     
     
         9 . A method of treating a subject, comprising:
 determining the presence or absence of at least one Tph2 mutation in said subject; and then, if said subject possesses at least one Tph2 mutation;   treating said subject for a serotonergic neurotransmission dysregulation disorder.   
     
     
         10 . The method of  claim 9 , wherein said disorder is depressive disorder. 
     
     
         11 . The method of  claim 9 , wherein said disorder is anxiety disorder. 
     
     
         12 . The method of  claim 9 , wherein said disorder is obsessive compulsive disorder. 
     
     
         13 . The method of  claim 9 , wherein said treating step is carried out by administering a serotonin enhancer in an amount effective to treat said disorder. 
     
     
         14 . The method of  claim 13 , wherein said serotonin enhancer is selected from the group consisting of serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, and pharmaceutically acceptable salts thereof. 
     
     
         15 . The method of  claim 9 , wherein said Tph2 is human Tph2 and said mutation encodes a change in an amino acid of the encoded protein, said amino acid selected from the group consisting of A65, V66, F68, L77, F84, I94, R97, E105, P152, W153, P155, D162, L175, R191, E211, V223, P244, G251, 8276, P277, V278, R285, R294, P308, Y310, E313, A333, I339, A342, S343, L344, A346, K353, V421, E423, A428, A436, R441, Y446, P449, Y450, and Q468. 
     
     
         16 . The method of  claim 9 , wherein said Tph2 mutation is selected from the group consisting of the human P449R mutation, the human R441H mutation, the human W153R mutation, the human A65V mutation, the human V66I mutation, the human L175V mutation, and the human Q468X (where X is a stop codon) mutation. 
     
     
         17 .- 24 . (canceled) 
     
     
         25 . A method for stratifying a subject in a subgroup of a clinical trial of a therapy for the treatment of a serotonergic neurotransmission dysregulation disorder, said method comprising determining the genotype of the tryptophan hydroxylase 2 gene of said subject, wherein said subject is stratified into a subgroup for said clinical trial of said therapy based upon said subject's tryptophan hydroxylase 2 genotype. 
     
     
         26 . The method of  claim 25 , wherein said therapy is a serotonin enhancer therapy. 
     
     
         27 . The method of  claim 26 , wherein said serotonin enhancer is selected from the group consisting of serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, and pharmaceutically acceptable salts thereof. 
     
     
         28 . The method of  claim 25 , wherein said Tph2 is human Tph2 and genotype is characterized by a mutation that a change in an amino acid of the encoded protein, said amino acid selected from the group consisting of A65, V66, F68, L77, F84, I94, R97, E105, P152, W153, P155, D162, L175, R191, E211, V223, P244, G251, R276, P277, V278, R285, R294, P308, Y310, E313, A333, I339, A342, S343, L344, A346, K353, V421, E423, A428, A436, R441, Y446, P449, Y450, and Q468. 
     
     
         29 . The method of  claim 25 , wherein said Tph2 genotype is characterized by a Tph2 mutation is selected from the group consisting the human P449R mutation, the human R441H mutation, the human W153R mutation, the human A65V mutation, the human V66I mutation, the human L175V mutation, and the human Q468X (where X is a stop codon) mutation. 
     
     
         30 .- 43 . (canceled)