14 research outputs found
A case series in patients with enteropathy and granulomatous diseases
Background Although sarcoidosis and celiac disease are both chronic
immunologic disorders involving multiple organ systems, reports about
association of diseases in individual patients are sparse. While sarcoidosis
is a chronic granulomatous disease presumably reflecting an exaggerated
response to an unknown antigen, celiac disease is a T cell-driven disease
triggered by ingestion of gluten, a protein composite found in wheat and
related grains. Case presentation We present three cases with a longstanding
history of sarcoidosis that have been additionally diagnosed with celiac-like
enteropathy. In two cases, celiac disease was established applying celiac-
specific serology and duodenal histology, while one case was revealed as an
AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was
confirmed in both celiac patients, hence confirming previous data of linkage
disequilibrium as a cause for disease association. Remarkably, one celiac
patient presented with granulomatous nodulae in the ileum, thus reflecting an
intestinal sarcoid manifestation. In contrast the patient with an autoimmune
enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. Conclusions
Associations of sarcoidosis and celiac disease are rare but do occur.
Determining the HLA status in patients with complex autoimmune associations
might help classifying involved disease entities
Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders
The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders
A motor neuron disease–associated mutation in p150Glued perturbs dynactin function and induces protein aggregation
The microtubule motor cytoplasmic dynein and its activator dynactin drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the p150Glued subunit of dynactin results in the specific degeneration of motor neurons. This mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of p150Glued for microtubules and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the CAP-Gly domain, resulting in aggregation of the p150Glued protein both in vitro and in vivo, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death
Visual backward masking deficits in schizophrenic patients are associated with polymorphisms in the nicotinic receptor alpha 7 subunit gene (CHRNA7)
Visual backward masking (BM) deficits are often proposed to be trait markers for schizophrenia, revealing the genetic underpinnings of the disease. Here, we show that masking deficits in the shine-through effect are associated with polymorphisms in the nicotinic receptor 7 subunit gene (CHRNA7). In the shine-through effect, two vertical bars are slightly offset in the horizontal direction. Observers indicate this offset direction. When the vernier is followed by a grating, vernier offset discrimination deteriorates for controls but much more strongly for the patients. We found these masking deficits of the patients to be strongly correlated with mutations on the rs904952 SNP and a related haplotype. The results further support the significance of CHRNA7 as an important candidate gene for schizophrenia. We propose that because of the deficient cholinergic system, the neural activity of the vernier briefly presented cannot be enhanced and is vulnerable to masking
Smoking, but not malnutrition, influences promoter-specific DNA methylation of the proopiomelanocortin gene in patients with and without anorexia nervosa
Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we report the identification of four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the first example of an aminoacyl tRNA synthetase being implicated in a human genetic disease, which makes genes that encode these enzymes relevant candidates for other inherited neuropathies and motor neuron diseases
DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)
Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing