👤 A Spicer

Cardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry identified familial, syndromic, or metabolic causes in 30% of children. However, these results predated clinical genetic testing. We determined the prevalence of familial, syndromic, or metabolic causes in 83 consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006 to 2009. Seventy-six percent of probands (n = 63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n = 18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%; n = 7) and metabolic (26%; n = 11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%; n = 5) and metabolic (16%; n = 4) causes, but fewer familial cases (24%; n = 6) compared with HCM patients. The cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in >35% of children with HCM or DCM. Identification of etiology is important for management, family-based risk assessment, and screening. Show less

Decay-accelerating factor (DAF) is a membrane regulator of C3 activation that protects self cells from autologous complement attack. In humans, DAF is uniformly expressed as a glycosylphosphatidylinositol (GPI)-anchored molecule. In mice, both GPI-anchored and transmembrane-anchored DAF proteins are produced, each of which can be derived from two different genes (Daf1 and Daf2). In this report, we describe a Daf1 gene knock-out mouse arising as the first product of a strategy for targeting one or both Daf genes. As part of the work, we characterize recently described monoclonal antibodies against murine DAF protein using deletion mutants synthesized in yeast, and then employ the monoclonal antibodies in conjunction with wild-type and the Daf1 knock-out mice to determine the tissue distribution of the mouse Daf1 and Daf2 gene products. To enhance the immunohistochemical detection of murine DAF protein, we utilized the sensitive tyramide fluorescence method. In wild-type mice, we found strong DAF labelling of glomeruli, airway and gut epithelium, the spleen, vascular endothelium throughout all tissues, and seminiferous tubules of the testis. In Daf1 knock-out mice, DAF labelling was ablated in most tissues, but strong labelling of the testis and splenic dendritic cells remained. In both sites, reverse transcription-polymerase chain reaction analyses identified both GPI and transmembrane forms of Daf2 gene-derived protein. The results have relevance for studies of in vivo murine DAF function and of murine DAF structure. Show less