| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q21.1 | {?Attention deficit-hyperactivity disorder, susceptibility to, 7} | 613003 | 3 | TPH2 | 607478 |
A number sign (#) is used with this entry because of evidence that susceptibility to attention deficit-hyperactivity disorder-7 (ADHD7) is caused by mutation in the TPH2 gene (607478) on chromosome 12q21. One such family has been reported.
For a phenotypic description and a discussion of genetic heterogeneity of attention deficit-hyperactivity disorder, see 143465.
McKinney et al. (2008) reported a Norwegian woman with ADHD and a history of major depression. Her daughter also had ADHD. Both reported an excellent response to stimulant medication. Both patients had normal developmental histories.
Walitza et al. (2005) investigated the effect of polymorphic variants in the TPH2 gene, which maps to chromosome 12q, in 225 children with ADHD in 103 families. Three SNPs in and downstream of the transcriptional control region were assessed using the pedigree disequilibrium test. Preferential transmissions were detected for 2 of the SNPs (rs4570625, p = 0.049; rs11178997, p = 0.034). Haplotype analysis revealed a trend of association between these 2 SNPs and ADHD (p = 0.064).
In a Norwegian mother and daughter with ADHD, McKinney et al. (2008) identified a heterozygous mutation in the TPH2 gene (R303W; 143465.0002). In vitro functional expression studies showed that the mutant protein had less than 5% residual enzyme activity and decreased solubility, compatible with a folding defect or increased hydrophobicity of the mutant protein. McKinney et al. (2008) concluded that a loss-of-function TPH2 mutation leads to reduced serotonin synthesis, which may result in increased susceptibility to ADHD and possibly other psychiatric disorders.
McKinney, J., Johansson, S., Halmoy, A., Dramsdahl, M., Winge, I., Knappskog, P. M., Haavik, J. A loss-of-function mutation in tryptophan hydroxylase 2 segregating with attention-deficit/hyperactivity disorder. (Letter) Molec. Psychiat. 13: 365-367, 2008. [PubMed: 18347598] [Full Text: https://doi.org/10.1038/sj.mp.4002152]
Walitza, S., Renner, T. J., Dempfle, A., Konrad, K., Wewetzer, C., Halbach, A., Herpertz-Dahlmann, B., Remschmidt, H., Smidt, J., Linder, M., Flierl, L., Knolker, U., Friedel, S., Schafer, H., Gross, C., Hebebrand, J., Warnke, A., Lesch, K. P. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Molec. Psychiat. 10: 1126-1132, 2005. [PubMed: 16116490] [Full Text: https://doi.org/10.1038/sj.mp.4001734]