Furer A.,Tel Aviv Medical Center |
Furer A.,Israel Defense Forces |
Afek A.,Israel Ministry of Health |
Afek A.,Tel Aviv University |
And 12 more authors.
PLoS ONE | Year: 2015
Background: Short stature was suggested as a risk factor for diabetes onset among middle age individuals, but whether this is the case among young adults is unclear. Our goal was to assess the association between height and incident diabetes among young men. Background Short stature was suggested as a risk factor for diabetes onset among middle age individuals, but whether this is the case among young adults is unclear. Our goal was to assess the association between height and incident diabetes among young men. Methods and Findings: Incident diabetes was assessed among 32,055 men with no history of diabetes, from the prospectively followed young adults of the MELANY cohort. Height was measured at two time points; at adolescence (mean age 17.4±0.3 years) and grouped according to the USCDC percentiles and at young adulthood (mean age 31.0±5.6 years). Cox proportional hazards models were applied. There were 702 new cases of diabetes during a mean follow-up of 6.3±4.3 years. There was a significant increase in the crude diabetes incidence rate with decreasing adolescent height percentile, from 4.23 cases/104 person-years in the <10th percentile group to 2.44 cases/104 person-years in the 75th≤ percentile group. These results persisted when clinical and biochemical diabetes risk factors were included in multivariable models. Compared to the 75th≤ percentile group, height below the 10th percentile was associated with a hazard ratio (HR) of 1.64 (95%CI 1.09-2.46, p = 0.017) for incident diabetes after adjustment for age, body mass index (BMI), fasting plasma glucose, HDL-cholesterol and triglyceride levels, white blood cells count, socioeconomic status, country of origin, family history of diabetes, sleep quality and physical activity. At age 30 years, each 1-cm decrement in adult height was associated with a 2.5% increase in diabetes adjusted risk (HR 1.025, 95%CI 1.01-1.04, p = 0.001). Copyright: © 2015 Furer et al. Source
Magen S.,Ben - Gurion University of the Negev |
Magnani R.,University of Kentucky |
Haziza S.,Ben - Gurion University of the Negev |
Hershkovitz E.,Pediatric Endocrinology and Metabolism Unit |
And 3 more authors.
PLoS ONE | Year: 2012
Deletion of the first exon of calmodulin-lysine N-methyltransferase (CaM KMT, previously C2orf34) has been reported in two multigene deletion syndromes, but additional studies on the gene have not been reported. Here we show that in the cells from 2p21 deletion patients the loss of CaM KMT expression results in accumulation of hypomethylated calmodulin compared to normal controls, suggesting that CaM KMT is essential for calmodulin methylation and there are no compensatory mechanisms for CaM methylation in humans. We have further studied the expression of this gene at the transcript and protein levels. We have identified 2 additional transcripts in cells of the 2p21 deletion syndrome patients that start from alternative exons positioned outside the deletion region. One of them starts in the 2nd known exon, the other in a novel exon. The transcript starting from the novel exon was also identified in a variety of tissues from normal individuals. These new transcripts are not expected to produce proteins. Immunofluorescent localization of tagged CaM KMT in HeLa cells indicates that it is present in both the cytoplasm and nucleus of cells whereas the short isoform is localized to the Golgi apparatus. Using Western blot analysis we show that the CaM KMT protein is broadly expressed in mouse tissues. Finally we demonstrate that the CaM KMT interacts with the middle portion of the Hsp90 molecular chaperon and is probably a client protein since it is degraded upon treatment of cells with the Hsp90 inhibitor geldanamycin. These findings suggest that the CaM KMT is the major, possibly the single, methyltransferase of calmodulin in human cells with a wide tissue distribution and is a novel Hsp90 client protein. Thus our data provides basic information for a gene potentially contributing to the patient phenotype of two contiguous gene deletion syndromes. © 2012 Magen et al. Source
Muhammad E.,Ben - Gurion University of the Negev |
Leventhal N.,Pediatric Endocrinology and Metabolism Unit |
Leventhal N.,Ben - Gurion University of the Negev |
Parvari G.,Technion - Israel Institute of Technology |
And 18 more authors.
Human Genetics | Year: 2011
Genetic disorders of excessive salt loss from sweat glands have been observed in pseudohypoaldosteronism type I (PHA) and cystic fibrosis that result from mutations in genes encoding epithelial Na+ channel (ENaC) subunits and the transmembrane conductance regulator (CFTR), respectively. We identified a novel autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration. Three affected individuals from a small Bedouin clan presented with failure to thrive, hyponatremic dehydration and hyperkalemia with isolated sweat salt wasting. Using positional cloning, we identified the association of a Glu143Lys mutation in carbonic anhydrase 12 (CA12) with the disease. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the reversible hydration of carbon dioxide to form a bicarbonate anion and a proton. Glu143 in CA12 is essential for zinc coordination in this metalloenzyme and lowering of the protein-metal affinity reduces its catalytic activity. This is the first presentation of an isolated loss of salt from sweat gland mimicking PHA, associated with a mutation in the CA12 gene not previously implicated in human disorders. Our data demonstrate the importance of bicarbonate anion and proton production on salt concentration in sweat and its significance for sodium homeostasis. © 2010 Springer-Verlag. Source
Messinger Y.H.,Pediatric Hematology Oncology |
Mendelsohn N.J.,Medical Genetics |
Rhead W.,Medical College of Wisconsin |
Dimmock D.,Medical College of Wisconsin |
And 11 more authors.
Genetics in Medicine | Year: 2012
Purpose: Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. Methods: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. Results: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. Conclusion: The combination of rituximab with methotrexate intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the nave setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy. © 2012 American College of Medical Genetics. Source