L M Bekris

Publications (8)33.55 Total impact

• Article: Mutations in the TSGA14 gene in families with autism spectrum disorders.

  O Korvatska, A Estes, J Munson, G Dawson, L M Bekris, R Kohen, C-E Yu, G D Schellenberg, W H Raskind
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  ABSTRACT: Linkage to 7q has been the most robust genetic finding in familial autism. A previous scan of multiplex families with autism spectrum disorders found a linkage signal of genome-wide significance at D7S530 on 7q32. We searched a candidate imprinted region at this location for genetic variants in families with positive linkage scores. Using exon resequencing, we identified three rare potentially pathogenic variants in the TSGA14 gene, which encodes a centrosomal protein. Two variants were missense mutations (c.664C>G; p.P206A and c.766T>G; p.C240G) that changed conserved residues in the same protein domain; the third variant (c.192+5G>A) altered splicing, which resulted in a protein with an internal deletion of 16 residues and a G33D substitution. These rare TSGA14 variants are enriched in the affected subjects (6/348 patients versus 2/670 controls, Fisher's exact two tailed P = 0.022). This is the first report of a possible link of a gene with a centrosomal function with familial autism.
  American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2011; 156B(3):303-11. · 3.70 Impact Factor
• Article: Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

  L M Bekris, N M Galloway, S Millard, D Lockhart, G Li, D R Galasko, M R Farlow, C M Clark, J F Quinn, J A Kaye, G D Schellenberg, J B Leverenz, P Seubert, D W Tsuang, E R Peskind, C E Yu
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  ABSTRACT: The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPβ or Aβ42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPβ, and Aβ42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.
  Neurobiology of aging 12/2010; 32(3):556.e13-23. · 5.94 Impact Factor
• Article: Changes in GAD65Ab-specific antiidiotypic antibody levels correlate with changes in C-peptide levels and progression to islet cell autoimmunity.

  E Ortqvist, B Brooks-Worrell, K Lynch, J Radtke, L M Bekris, I Kockum, C-D Agardh, C M Cilio, A L Lethagen, B Persson, A Lernmark, J Reichow, S Oak, J P Palmer, C S Hampe
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  ABSTRACT: The previously reported absence of 65-kDa glutamate decarboxylase antibody (GAD65Ab)-specific antiidiotypic antibodies (anti-Id) in type 1 diabetes (T1D) patients at clinical onset could be due to an inability to mount an antibody response to GAD65Ab or a longitudinal decline in anti-Id levels. We investigated anti-Id levels in longitudinal samples obtained from T1D patients (n = 41) (clinical diagnosis - 12 months), and latent autoimmune diabetes in adults (LADA) patients (n = 32) who received alum-formulated human recombinant GAD65 (baseline - 12 months). We also determined anti-Id levels in a small cohort of Type 2 diabetes patients during their development of autoimmune T cell responses. At clinical onset T1D patients presented no or low anti-Id levels. However, 22/41 T1D patients showed ≥50% increase in GAD65Ab-specific anti-Id levels during follow-up; peaking at 3 (n = 1), 6 (n = 10), 9 (n = 10), or 12 (n = 1) months. Increasing anti-Id levels marked patients who experienced a temporary increase in C-peptide levels. Anti-Id levels correlated significantly with glycated hemoglobin and C-peptide levels at 6 and 9 months (P values ranged from <0.001 to <0.05). In LADA patients receiving placebo, anti-Id levels declined in seven of nine patients, whereas four of five patients receiving 20 μg alum-formulated human recombinant GAD65 showed increasing anti-Id levels. Changes in anti-Id and C-peptide levels closely correlated (P < 0.0001). The significant decline in anti-Id levels (P = 0.03) in T2D patients developing T cell autoimmune responses supports our hypothesis that declining anti-Id levels are associated with developing islet autoimmunity. The close association between GAD65Ab-specific anti-Id levels and β-cell function may provide a novel marker for the progression of autoimmune diabetes.
  The Journal of clinical endocrinology and metabolism 11/2010; 95(11):E310-8. · 6.50 Impact Factor
• Article: GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination.

  L M Bekris, R A Jensen, E Lagerquist, T R Hall, C-D Agardh, C M Cilio, A L Lethagen, A Lernmark, J A Robertson, C S Hampe
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  ABSTRACT: Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 microg alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-microg dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. Our data suggest that the apparent beneficial effects of 20 microg alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern.
  Diabetic Medicine 06/2007; 24(5):521-6. · 2.90 Impact Factor
• Article: Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels.

  L M Bekris, C Shephard, M Janer, J Graham, B McNeney, J Shin, M Zarghami, W Griffith, F Farin, T J Kavanagh, A Lernmark
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  ABSTRACT: The purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies. T1D patients and control subjects from the Swedish Childhood Diabetes Registry and the Swedish Diabetes Incidence Study registry were genotyped for two GCLC promoter polymorphisms; the GCLC -129 C to T single nucleotide polymorphism (GCLC -129 SNP) and the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR). Glutamate decarboxylase antibody (GAD65Ab) positive T1D patients with the GCLC -129 SNP C/T genotype have increased GAD65Ab levels (p-value, <0.05) compared to the GCLC -129 SNP C/C genotype. T1D patients with an age-at-onset of 14-35 years who possess the GCLC -129 SNP T/T genotype have a higher GAD65Ab index than T1D patients with the GCLC -129 SNP C/C genotype (p-value <0.05). In addition, T1D patients with an age-at-onset of 14-35 years possess the GCLC TNR 7/8 genotype at a lower frequency than the control subjects (OR, 0.33, 95% CI, 0.13-0.82). The GCLC -129 SNP and GCLC TNR appear to be in linkage disequilibrium (p-value<0.0001). These results suggest that GCLC promoter polymorphisms may influence GAD65Ab levels and may influence the age at which T1D is diagnosed.
  Experimental and Clinical Endocrinology &amp Diabetes 05/2007; 115(4):221-8. · 1.69 Impact Factor
• Article: A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.

  J B Leverenz, C E Yu, T J Montine, E Steinbart, L M Bekris, C Zabetian, L K Kwong, V M-Y Lee, G D Schellenberg, T D Bird
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  ABSTRACT: Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.
  Brain 05/2007; 130(Pt 5):1360-74. · 9.46 Impact Factor
• Article: Targeting type 1 diabetes before and at the clinical onset of disease.

  L M Bekris, T J Kavanagh, A Lernmark
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  ABSTRACT: Autoimmune type 1 diabetes is strongly associated with a number of immune abnormalities that manifest themselves before and at the time of clinical diagnosis. The clinical onset is associated with a major loss of the pancreatic islet beta cells. Insulin treatment is the only treatment option since numerous trials with agents that suppress or modulate immune function have failed to preserve beta cell function long term. Recent studies suggest that it is possible to predict clinical onset of diabetes by combining genetic with autoantibody testing. In this review we will summarize current and future drug targets for subjects at risk for type 1 diabetes as well as for subjects with recent onset disease. We will also discuss the possible importance of initiating as well as contributing factors such as reactive oxygen species and modified autoantigens. It is speculated that drug targets of factors important to disease pathogenesis may provide safe and effective adductive treatment to preserve beta cell function in autoantibody positive subjects who are at maximum risk for disease.
  Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 04/2006; 6(1):103-24.
• Article: Epitope analysis of insulin autoantibodies using recombinant Fab.

  C J Padoa, N J Crowther, J W Thomas, T R Hall, L M Bekris, C Torn, M Landin-Olsson, E Ortqvist, J P Palmer, A Lernmark, C S Hampe
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  ABSTRACT: Autoantibodies to insulin are often the first autoantibodies detected in young children with type 1 diabetes and can be present before the onset of clinical diabetes. These autoantibodies and their epitopes are, however, not well characterized. We explored the use of monoclonal antibodies and their recombinant Fab as reagents for epitope analysis. In this study we cloned and characterized the recombinant Fab of the insulin-specific monoclonal antibody CG7C7. We found the epitope of this antibody to be located predominantly at the A-chain loop of the insulin molecule. The recombinant Fab was then used to compete for insulin binding against insulin autoantibodies present in sera from patients with type 1 or type 1.5 diabetes. In competition experiments with sera positive for autoantibodies to insulin the recombinant Fab significantly reduced the binding to [125I]-insulin by sera of type 1 (n = 35) and type 1.5 diabetes [latent autoimmune diabetes in adults (LADA)] (n = 14) patients (P < 0.0001). We conclude that competition between insulin-specific monoclonal antibodies or their recombinant Fab and insulin autoantibodies should prove useful in the epitope analysis of autoantibodies to insulin.
  Clinical & Experimental Immunology 06/2005; 140(3):564-71. · 3.36 Impact Factor