Elsevier

Genomics

Volume 42, Issue 2, 1 June 1997, Pages 331-335
Genomics

SHORT COMMUNICATION
Human Cholecystokinin Type A Receptor Gene: Cytogenetic Localization, Physical Mapping, and Identification of Two Missense Variants in Patients with Obesity and Non-Insulin-Dependent Diabetes Mellitus (NIDDM)

https://doi.org/10.1006/geno.1997.4749Get rights and content

Abstract

The human CCKAR gene was previously mapped to chromosome 4 using a panel of human/hamster somatic cell hybrids. We now report the cytogenetic and physical localization of the CCKAR gene. Using fluorescencein situhybridization, we determined that CCKAR maps to 4p15.1–p15.2. On the physical map, CCKAR was adjacent to the marker AFMa283yh5, between AFMb355ya5 and WI-4086. A simple sequence repeat (D4S391) with high heterozygosity was found in the database, and CCKAR and this genetic marker were colocalized on two YACs (933D9 and 928A5). We also characterized the genomic structure and determined the exon–intron boundaries of the gene. This provided the opportunity to screen the gene in patients with non-insulin-dependent diabetes mellitus and/or obesity for single nucleotide changes using a single-strand conformational polymorphism strategy. Five sequence variants were identified in the coding sequence of the gene, including two missense variants (G21R and V365I). The results of these studies provide (1) precise genetic and physical mapping data, (2) exon–intron sequences for single nucleotide analysis, and (3) identification of two missense mutations in the CCKAR gene. The contribution of these CCKAR variants to normal physiology, to obesity, and to diabetes can now be evaluated.

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  • Effects of nerve growth factor (NGF), fluoxetine, and amitriptyline on gene expression profiles in rat brain

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    The relationship between this system and depression is not unknown as somatostatin 2 and 3 receptor agonists result in antidepressant-like effects in the forced swim test (Engin and Treit, 2009). CCKAR, on the other hand, has primarily been a target for understanding obesity (Inoue et al., 1997). Despite often suggestive findings, none of the four genes significantly altered by NGF (but not by the two established antidepressants) as compared with the saline controls is presently considered a primary candidate for depression etiology or antidepressant action.

  • Evidence of a Novel Quantitative-Trait Locus for Obesity on Chromosome 4p in Mexican Americans

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    In addition, CCK-like peptides are endogenous signals that are mediated by CCKA receptors, involved in the control of food intake in humans (Gutzwiller et al. 2000). Using a single-strand conformational polymorphism strategy, Inoue et al. (1997) identified five sequence variants, including two missense variants in patients with T2D and obesity, which may be influencing obesity and diabetes. Moran and coworkers (1998) showed that rats that do not express CCKA receptors develop obesity, hyperglycemia, and T2D.

  • A major predisposition locus for severe obesity, at 4p15-p14

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    The human draft genomic sequence around D4S3350 contains no obvious obesity-related candidate genes in the region (International Human Genome Sequencing Consortium 2001; Venter et al. 2001). Of the genes that previously have been implicated in obesity, CCKAR (cholecystokinin A receptor) (Ulrich et al. 1993; Miller et al. 1995; Inoue et al. 1997; Funakoshi et al. 2000) is the one closest to this region. However, in light of the position of this gene, we do not think that it will explain this linkage.

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J. R. J. ReeveV. EysseleinT. E. SolomonV. L. W. Go, Eds.

1

To whom correspondence should be addressed at the Division of Endocrinology, Diabetes, and Metabolism, Washington University School of Medicine, 660 South Euclid, Campus Box 8127, St. Louis, MO 63110. Telephone: (314) 362-8680. Fax: (314) 362-4833. E-mail: [email protected].

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