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Association Between a Null Mutation in the Human Ciliary Neurotrophic Factor (CNTF) Gene and Increased Incidence of Psychiatric Diseases?

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Association Between a Null Mutation in the Human Ciliary Neurotrophic Factor (CNTF) Gene and Increased Incidence of Psychiatric Diseases? ELSEVIER Neuroscience Letters 203 (1996) 109-110 Association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and increased incidence of psychiatric diseases? Johannes Thome a,*, Johannes Kornhuber a, Alessandra Baumer b, Michael R6sler a, Helmut Beckmann a, Peter Riederer a aDepartment of Psychiatry, University of Wfirzburg, Fiichsleinstrafle 15, 97080 Wfirzburg, Germany blnstitute of Human Genetics, University of Wfirzburg, Am Hubland, 97074 Wiirzburg, Germany Received 16 October 1995; revised version received 6 December 1995; accepted 6 December 1995 Abstract We report a possible association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and psychiatric dis- eases. Prior findings that the mutant allele frequency is not significantly elevated in patients suffering from neurological diseases are confirmed. The frequency of the mutant allele was higher among psychiatric patients (0.192, n = 297) than among healthy controls and neurological patients (0.142, n = 267). This difference (one-tailed 2 x 2 chi-square test, P < 0.05) might be evidence that disturbances in the neurotrophic factor system could play a crucial role in the etiopathogenesis of psychiatric disorders, mainly psychoses. Keywords: Ciliary neurotrophic factor; Genetics; Mutation; Neurodevelopment; Neurotrophic factor; Psychiatry; Psychoses Neurodevelopmental deficits, disturbances of the quency in a Caucasian population was determined for the cell migration and dysconnections of neuronal and glial first time. structures are currently discussed as possible pathome- Inpatients (208 neurological: 112 female, 96 male; chanisms for psychiatric disorders, mainly endogenous and 297 psychiatric: 155 female, 142 male) suffering psychoses including schizophrenia [2,3,9] and manic- from various diseases, as well as 59 age- and sex-matched depressive disorders, severe brain diseases with until now healthy subjects (31 female, 28 male) were examined unknown pathogenesis and putative genetic and environ- (mean age __. SD, 43.5 __. 17.2 years). Since no differences mental influences Neurotrophic factors (NTFs) such as in the allele frequencies between neurological patients the ciliary neurotrophic factor (CNTF) play a central role and healthy persons have been reported [8] and since such in the regulation of neural development. Recently, a null- differences could also not be found in our sample, the mutation in the CNTF gene, which is located on chromo- control group consisted of neurological patients and some 11, was described [5,6,8]. Homozygote mutants healthy persons, whereas the index group was represented lack CNTF completely, whereas heterozygotes may have by the patients suffering from psychiatric diseases. a reduced CNTF level. While the allele frequency in neu- For genotyping, genomic DNA was extracted from rological patients has been reported to be comparable to whole blood of each individual. Polymerase chain reac- those of healthy individuals, the allele frequency in pa- tion (PCR) amplification of DNA was conducted with tients with psychiatric disorders has not yet been investi- primers flanking the gene region containing the mutation gated. Therefore, the aims of the present study were to (forward primer from 1067-1090 in the intron: 5'-GCC investigate the frequency of this mutation in a group of AGT GAG ATG AGT GAG AT]" T'FG-3'; and reverse psychiatric patients and to answer the question whether primer from 1176--1200 in the second exon: 5'-CAG G'I~ persons with CNTF mutation show possibly a higher risk GAT GTT CTF G'Iq" CAT GCC C-3'). DNA was ampli- for psychiatric diseases. Simultaneously, the allele fre- fied in 25/d containing 2.5/xl 10 x PCR-buffer (100 mM Tris-HCl, 15 mM MgC12, 500 mM KC1, pH 8.3), 0.5/xl dNTP (10 mM), 2.5/tl of each primer (20 pmol//xl) and * Corresponding author. Tel.: +49 931 2031; fax: +49 931 203425. 1 U Taq DNA Polymerase. The PCR conditions consisted 0304-3940/96/$12.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3940(95)12274-5 110 J. Thome et al. / Neuroscience Letters 203 (1996) 109-110 Table 1 On the assumption of Hardy-Weinberg equilibrium and Genotypes and allele frequencies of the null-mutution in the CNTF an allele-M frequency of 0.168 (total sample, n =564), gene in the control group (neurological patients and healthy persons) the expected number of homozygotes for the null muta- and in psychiatric patients tion is 16 in the total sample, though the observed fre- quency is only seven. This finding, already seen in an Controls (n = 267) Psychiatric (healthy persons and patients(n = 297) other sample [8], might be evidence that the M/M- neurological patients) genotype is associated with a significantly increased pre- or perinatal mortality [10]. Genotype Very recently, associations were found between vari- N/N, n (%) 194 (72.7) 187 (63.0) ants in a neurotrophin gene (NT3) and schizophrenia and N/M, n (%) 70 (26.2) 106 (35.7) M/M, n (%) 3 (1.1) 4 (1.3) schizophrenic subgroups, respectively [ 1,7]. The fact that these mutations can be found in healthy persons as well Allele frequency (M) 0.142 0.192" may be explained by the strong pleiotropia and redun- dancy among NTFs [4]. Further studies are needed for The frequency of the mutant allele in the two groups differs signifi- revealing the relevance of possible NTF deficits in psy- cantly (*P < 0.05, one-tailed 2 x 2 chi-square tes0. chiatric diseases. Currently, we are genotyping more sub- jects in order to find possible subgroups with extremely of an initial denaturation step for 4 min at 95°C, 30 cycles high mutant allele frequencies among psychiatric patients. of 1 min at 94°C, 1 min at 60°C, and 2 min at 72°C, fol- Moreover, we try to correlate the different genotypes with lowed by a final extension step for 5 min at 72°C. For clinical data such as age of onset, duration of illness, and allele detection, the PCR product with a molecular weight family history. First preliminary results suggest that such of 134 bp was digested with the restriction endonuclease a high-risk group could be constituted from patients suf- HaeIII. Fragments were separated by electrophoresis on fering from schizophrenic psychoses. As the importance an ethidium bromide-stained agarose gel (3%) and ana- of examining the etiopathogenesis of these diseases can- lyzed under UV light. The single genotypes (N/N, nor- not be overemphasized, further investigations are needed mal; N/M, heterozygote mutant; M/M, homozygote mu- to replicate or to refute our findings. tant) showed characteristic bands at the following molecu- lar weights: N/N, 94bp, 40bp; N/M, 134bp, 94bp, [1] Hattori, M. and Nanko, S., Association of neurotrophin-3 gene 40 bp; M/M, 134 bp (no digestion). variant with severe forms of schizophrenia, Biochem. Biophys. The frequency of the mutation was significantly in- Res. Commun., 209 (1995) 513-518. creased in psychiatric patients when compared to healthy [2] Jakob, H. and Beckmann, H., Prenatal developmental distur- persons and neurological patients as controls (one-tailed bances in the limbic allocortex in schizophrenics, J. Neural Transm., 65 (1986) 303-326. 2 x 2 chi-square test; P < 0.05). The frequency of the [3] Jones, P. and Murray, R.M., The genetics of schizophrenia is the mutated allele was 0.192 in psychiatric patients and 0.142 genetics of neurodevelopment, Br. J. Psychiatry, 158 (1991) 615- in the control group (Table 1). The distribution of the 623. three genotypes in the neurological group did not differ [4] Korsching, S., The neurotrophic factor concept: a reexamination, significantly from those in the group with healthy per- J. Neurosci., 13 (1993) 2739-2748. [5] Lam, A., Fuller, F., Miller, J., Kloss, J., Manthorpe, M., Varon, S. sons. The four homozygote mutation carriers of the psy- and Cordell, B., Sequence and structural organization of the hu- chiatric group suffered from manic-depressive disorder man gene encoding ciliary neurotrophic factor, Gene, 102 (1991) (female, 51 years), hypochondriacal depression (male, 271-276. 53 years), severe alcohol dependence (male, 39 years) [6] Lev, A.A., Rosen, D.R., Kos, C., Clifford, E., Landes, G., Hauser, S.L. and Brown, Jr., R.H., Human ciliary neurotrophic factor: lo- and periodic catatonia (female, 35 years) respectively. calization to the proximal region of the long arm of chromosome The latter is a subtype of schizophrenic psychoses with 11 and association with CAJGT dinucleotide repeat, Genomics, 16 severe course and considerable familial inheritance. (1993) 539-541. A reduced level of NTFs could be an unspecific factor [7] Nanko, S., Hattori, M., Kuwata, S., Sasaki, T., Fukuda, R., Dal, of vulnerability, leading eventually, together with other X.Y., Yamaguchi, Y., Shibata, Y. and Kazamatsuri, H., Neurotro- phin-3 gene polymorphism associated with schizophrenia, Acta noxae such as environmental effects, intoxications, trau- Psyehiatr. Stand., 89 (1994) 390-392. mata, or other genetic defects, to disturbed development [8] Takahashi, R., Yokoji, H., Misawa, H., Hayashi, M., Hu, J. and and function of the CNS. On the other hand, it is also Deguchi, T., A null mutation in the human CNTF gene is not possible that a NTF (CNTF and/or others) lacking disor- causally related to neurological diseases, Nature Genet., 7 (1994) der underlies a specific subgroup of psychiatric diseases, 79-84. [9] Weinberger, D.R. and Lipska, B.K., Cortical maldevelopment, thereby defining them neurochemically as an entity. anti-psychotic drugs, and schizophrenia: a search for common A cue for the possible relevance of CNTF in the de- ground, Schizophrenia Res., 16 (1995) 87-110. veloping organism could be the following observation. [10] Wright, A.F. and Carothers, A.D., CNTF in the embryo, Nature Genet., 7 (1994) 460. .
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