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A CAV3 microdeletion differentially affects skeletal muscle and myocardium

From the I.R.C.C.S.E. Medea (Drs. Cagliani, Bresolin, and Sironi), Associazione La Nostra Famiglia, Bosisio Parini (LC), and Centro Dino Ferrari (Drs. Bresolin, Prelle, Gallanti, Fagiolari, Bonato, Galbiati, Corti, Lamperti, Moggio, and Comi, P. Ciscato, F. Fortunato), Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, I.R.C.C.S. Ospedale Maggiore Policlinico, and Centro di Eccellenza per le Malattie Neurodegenerative (Drs. Bresolin, Gallanti, and Comi), Milano, Italy.

Address correspondence and reprint requests to Dr. R. Cagliani, I.R.C.C.S. E. Medea, Associazione La Nostra Famiglia, Via Don Luigi Monza 20, 23842 Bosisio Parini (LC), Italy; e-mail: rcagliani{at}bp.lnf.it

Background: Caveolin-3 is the muscle-specific protein product of the caveolin gene family and an integral membrane component of caveolae. Mutations in the gene encoding caveolin-3 (CAV3) underlie four distinct disorders of skeletal muscle: the autosomal dominant form of limb–girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease (RMD), sporadic and familial forms of hyperCKemia, and distal myopathy.

Objective: To characterize a multigenerational Italian family affected by an autosomal dominant myopathic disorder and to assess the expression of caveolin-3, dystrophin, dystrophin-associated glycoproteins, and neuronal nitric oxide synthase in the myocardium of an affected patient.

Methods: Clinical analysis involved 15 family members. Skeletal muscle expression of sarcolemmal proteins was evaluated by immunohistochemistry and western blot analysis in three affected individuals. Caveolar structures were analyzed through electron microscopy in muscle biopsies and in one heart biopsy.

Results: CAV3 genetic analysis showed a heterozygous 3-bp microdeletion (328–330del) in affected individuals, resulting in the loss of a phenylalanine (Phe97del) in the transmembrane domain. In the skeletal muscle, the mutation was associated with severe caveolin-3 deficiency and caveolar disorganization, whereas the expression of the other analyzed muscle proteins was unaltered. Remarkably, caveolin-3 was expressed in myocardium at a level corresponding to about 60% of that of control individuals and was correctly localized at the myocardial cell membranes, with preservation of cardiac myofiber caveolar structures. Clinical analysis revealed the concomitant presence in this family of the following phenotypes: RMD, LGMD, and hyperCKemia.

Conclusions: Intrafamilial phenotypic heterogeneity is associated with caveolin-3 Phe97 microdeletion. The molecular network interacting with caveolin-3 in skeletal muscle and heart may differ.

Received February 7, 2003. Accepted in final form July 31, 2003.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the December 9 issue to find the title link for this article.

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