Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder.
Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor "cAMP-responsive element modulator" (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product "inducible cAMP early repressor" (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2-generating the ICER isoform-and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary.
Domschke
K
K
Department of Psychiatry, University of Münster, Münster, Germany.
Kuhlenbäumer
G
G
Schirmacher
A
A
Lorenzi
C
C
Armengol
L
L
DiBella
D
D
Gratacos
M
M
Garritsen
H S
HS
Nöthen
M M
MM
Franke
P
P
Sand
P
P
Fritze
J
J
Perez
G
G
Maier
W
W
Sibrowski
W
W
Estivill
X
X
Bellodi
L
L
Ringelstein
E B
EB
Arolt
V
V
Martin-Santos
R
R
Catalano
M
M
Stögbauer
F
F
Deckert
J
J
D000379:Agoraphobia / Q000235:genetics; D016022:Case-Control Studies; D051786:Cyclic AMP Response Element Modulator; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D016678:Genome; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D016584:Panic Disorder / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator