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      Isolated Cardiac Sarcoidosis Associated with the Expression of a Splice Variant Coding for a Truncated BTNL2 Protein

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          A 33-year-old woman presented with clinical signs of heart failure and previously diagnosed complete atrioventricular block. DNA sequencing revealed a homozygous point mutation in exon 5 of the btnl2 gene coding for a truncated protein which lacks the membrane-anchoring motif. This single nucleotide polymorphism is known to be a risk factor for sarcoidosis. Indeed, endomyocardial biopsy demonstrated multiple nonnecrotizing granulomas composed of epitheloid cells and moderate numbers of multinucleated giant cells. Because no other organs were affected, isolated cardiac sarcoidosis was diagnosed and treated with corticosteroids. Thus, detection of the disease-associated btln2 allele may help to identify patients with sarcoidosis as the underlying cause of heart failure.

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          Most cited references 11

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          Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

          Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.
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            Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies.

            An early diagnosis of cardiac sarcoidosis is important, particularly when considering the need for administering corticosteroid therapy. However, no reports are available on the success rate of diagnosis on the basis of biopsy findings in patients with cardiac sarcoidosis. This study investigated the diagnostic success rate of histologic evaluation of endomyocardial biopsy specimens in patients with this disease. Right ventricular endomyocardial biopsy was performed in 26 patients in whom cardiac sarcoidosis was strongly suspected according to the Diagnostic Criteria of Sarcoidosis, plus abnormalities on the electrocardiogram, cardiac radionuclide images, or in left ventricular wall motion. A mean of 4.0 sites were sampled per patient. In each case we determined whether a definitive diagnosis of cardiac sarcoidosis could be made histologically. Noncaseating granulomas were found in only 5 (19.2%) of the 26 cases, thus permitting a histologic diagnosis of cardiac sarcoidosis. A histologic diagnosis was made in 4 (36.4%) of 11 patients who exhibited a dilated cardiomyopathy-like clinical picture, in contrast to only 1 (6.7%) of 15 patients in whom conduction disturbances were the major clinical feature and whose left ventricular ejection fraction was within normal limits. The diagnostic rate achieved with biopsy in cardiac sarcoidosis is low; the patients with sarcoidosis and evidence of significant cardiac involvement should be treated for cardiac sarcoidosis despite negative myocardial biopsies for this disease.
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              Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis.

               Ori Lieberman (1975)
              The level of serum angiotensin-converting enzyme (ACE) was elevated in 15 of 17 patients with active sarcoidosis. Serum ACE was studied to determine the effect of chronic lung disease upon the blood level of an enzyme believed to originate from the lungs. The assay was performed in approximately 200 control subjects and 200 patients with chronic lung disease using hippuryl-L-histidyl-L-leucine as substrate. Enzyme activity greater in male control subjects than in female subjects of comparable age and greater in children than in adults. Serum ACE was significantly reduced in patients with chronic obstructive lung disease, lung cancer, tuberculosis and cystic fibrosis, as compared to control subjects, and was even lower in those receiving corticosteroids. Of greatest interest, however, was that levels in patients with active sarcoidosis not receiving steroids were greater than 2 standard deviations above the mean for the adult control subjects (greater than 11.6 units) whereas levels in patients with sarcoidosis receiving steroids and in those with resolved disease were normal. A survey of subjects with other granulomatous diseases failed to reveal any other condition that was significantly associated with a similar elevation of serum ACE levels. Elevation of ACE levels in sarcoidosis appears to be associated with the active disease process and does not appear to be a familial inherited enzyme abnormality. An assay of serum ACE is a useful tool for regulating therapy in sarcoidosis and for confirming the diagnosis, since it readily distinguishes these patients from others with tuberculosis, lung cancer or lymphoma.

                Author and article information

                S. Karger AG
                January 2008
                17 August 2007
                : 109
                : 2
                : 117-121
                Department of Internal Medicine-Cardiology, Philipps University of Marburg, Marburg, Germany
                105552 Cardiology 2008;109:117–121
                © 2007 S. Karger AG, Basel

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                Figures: 3, References: 15, Pages: 5
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