Molecular Genetics of the Caveolin Gene Family: Implications for Human Cancers, Diabetes, Alzheimer Disease, and Muscular Dystrophy Jeffrey A. Engelman,

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Molecular Genetics of the Caveolin Gene Family: Implications for Human Cancers, Diabetes, Alzheimer Disease, and Muscular Dystrophy Jeffrey A. Engelman, XiaoLan Zhang, Ferruccio Galbiati, Daniela Volonté, Federica Sotgia, Richard G. Pestell, Carlo Minetti, Philipp E. Scherer, Takashi Okamoto, Michael P. Lisanti The American Journal of Human Genetics Volume 63, Issue 6, Pages 1578-1587 (December 1998) DOI: 10.1086/302172 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Genomic organization of the caveolin gene family. The overall genomic organization of the murine caveolin gene family is shown; identical intron-exon boundaries have been reported for the human caveolin gene family (Engelman et al. 1998c,1998d). The American Journal of Human Genetics 1998 63, 1578-1587DOI: (10.1086/302172) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Alignment of the protein sequences and functional domains encoded by the last exon of murine Cav-1, -2, and -3. The positions of the oligomerization domain (single thin overline [Sargiacomo et al. 1995]), the caveolin-scaffolding domain (double thin overline [Li et al. 1996a; Couet et al. 19971997a,1997b,1997c]), the membrane-spanning domain (thick overline), and cysteines, conserved in caveolin-1 and -3, that are sites of palmitoylation (asterisks [*]) are shown. In addition, 10 of the 12 residues that are invariant between all known mammalian caveolins and caveolins from C. elegans (Tang et al. 1997) are localized to this last exon (boxes). Conserved residues that are deleted or mutated in human caveolin-3 and that lead to an autosomal dominant form of limb-girdle muscular dystrophy (Minetti et al. 1998) are indicated (underlines). The American Journal of Human Genetics 1998 63, 1578-1587DOI: (10.1086/302172) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 Human caveolin-1 and -2, located at the D7S522 locus (7q31.1), a known fragile site that is frequently deleted in human cancers. Location of the human caveolin-1 and -2 genes is shown with respect to the markers D7S486, D7S522, and the MET proto-oncogene (Engelman et al. 1998d). The smallest common deleted region (∼1,000 kb), as previously defined by LOH analysis, is shown. Note that D7S522 is located at the center of this region. More specifically, D7S522 is ∼500 kb downstream from the marker D7S486 and ∼500 kb upstream from the MET proto-oncogene. Given that the average insert size of the caveolin containing bacterial-artificial-chromosome genomic clones is ∼80–100 kb, the caveolin-1 and -2 genes must be located a maximum distance of ∼100 kb upstream or downstream of D7S522 (Engelman et al. 1998d). Thus, the position of the caveolin-1 and -2 genes lies at the center of this smallest common deleted region (Engelman et al. 1998d). The American Journal of Human Genetics 1998 63, 1578-1587DOI: (10.1086/302172) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Caveolin-3 and muscular dystrophy. Residues that are deleted or mutated in human caveolin-3 and that lead to a form of limb-girdle muscular dystrophy are indicated (boxes) [McNally et al. 1998; Minetti et al. 1998]). Note that three of the four mutations thus far identified cluster within the caveolin-scaffolding domain, a 20-amino-acid membrane proximal region of caveolin-3 (unbroken underline [McNally et al. 1998; Minetti et al. 1998]). One mutation occurs within the transmembrane domain (dashed underline [Minetti et al. 1998]). Prefixes to “Cav” are as follows”: m = mouse; r = rat; h = human. The American Journal of Human Genetics 1998 63, 1578-1587DOI: (10.1086/302172) Copyright © 1998 The American Society of Human Genetics Terms and Conditions