Cardiomyopathy (CM) is a primary degenerative disease of myocardium and is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (CM hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. Herein we show that both HCM and DCM hamsters share a common defect in a gene for ␦-sarcoglycan (␦-SG), the functional role of which is yet to be characterized. A breakpoint causing genomic deletion was found to be located at 6.1 kb 5 upstream of the second exon of ␦-SG gene, and its 5 upstream region of more than 27.4 kb, including the authentic first exon of ␦-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of ␦-SG transcripts with the consequent loss of ␦-SG protein in all the CM hamsters, despite the fact that the protein coding region of ␦-SG starting from the second exon was conserved in all the CM hamsters. We elucidated the molecular interaction of dystrophin-associated glycoproteins including ␦-SG, by using an in vitro pull-down study and ligand overlay assay, which indicates the functional role of ␦-SG in stabilizing sarcolemma. The present study not only identifies CM hamster as a valuable animal model for studying the function of ␦-SG in vivo but also provides a genetic target for diagnosis and treatment of human CM.Cardiomyopathy (CM) manifests dyspnea, cardiac failure, or sudden death, causing serious morbidity and mortality. Clinical features and molecular genetic studies of CM demonstrate a wide variety of possible genetic causes of this disease but the causative genes and pathogenesis are poorly understood (1-3). Medical treatment for this progressive disease are only palliative with poor prognosis. Syrian hamsters with CM are known to inherit both CM and muscular dystrophy as an autosomal recessive trait but the genetic cause still remains to be elucidated (4-6). Recent studies on muscular dystrophy revealed the genetic importance of sarcoglycans (SGs), a subcomplex of dystrophin-associated glycoprotein complex (DAGC), in this disease (7-10).Distinct sublines of Syrian hamster manifesting hypertrophic CM (HCM; BIO 14.6 and its descendant UMX7.1) or dilated CM (DCM; TO-2) have been established from the original line BIO1.50 (5, 6). We have reported to the DDBJ (DNA Data Base of Japan) that no mutation exists in the coding regions of cDNAs of BIO14.6 for ␣-, ␤-, or ␥-SGs, all of which are lost in cardiac and skeletal muscles of this animal, where dystrophin is normally expressed (11). Our latest study revealed that these SGs are also deficient in UMX7.1 and TO-2 (vide infra), suggesting a hypothesis that both HCM and DCM share the loss of SG subcomplex as a common causative feature in hamster. In addition, ␦-SG, which was identified recently, seemed to constitute DAGC together with ␣-, ␤-, and ␥-SGs (12). These facts prompted us to identify the causative gene common to HCM and DCM wit...

ABSTRACT:Andermann et al. described in 1972 an autosomal recessive inherited syndrome which associates agenesis of the corpus callosum, mental deficiency, and a peripheral motor deficit. We had the opportunity to study in detail 15 patients affected by this syndrome. As in the cases previously reported, the families of these children all originated from Charlevoix County and the Saguenay-Lac St-Jean area in the Province of Quebec.Clinically, these patients have a characteristic facies and moderate mental retardation associated with a progressive motor neuropathy leading to loss of ambulation by adolescence and progressive scoliosis. In 13 of these 15 patients, neuroradiological investigation has shown either total or partial agenesis of the corpus callosum. In every patient in whom these tests were done, sensory nerve action potentials were absent and motor nerve conduction velocities reduced. We also found neurogenic abnormalities both on EMG and neuromuscular biopsies. These abnormalities are similar to those described in Friedreich’s ataxia and in hereditary motor and sensory neuropathy type II, although in our patients the motor deficit is much more severe than in these diseases.The pathogenesis of the peripheral nervous system involvement is still unknown since there have so far been no autopsy studies of this syndrome.

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