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  • Title: Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder.
    Author: Domschke K, Kuhlenbäumer G, Schirmacher A, Lorenzi C, Armengol L, DiBella D, Gratacos M, Garritsen HS, Nöthen MM, Franke P, Sand P, Fritze J, Perez G, Maier W, Sibrowski W, Estivill X, Bellodi L, Ringelstein EB, Arolt V, Martin-Santos R, Catalano M, Stögbauer F, Deckert J.
    Journal: Am J Med Genet B Neuropsychiatr Genet; 2003 Feb; 117B(1):70-8. PubMed ID: 12555239.
    Abstract:
    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.
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