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Search Results: 1 - 10 of 4435 matches for " Louis Kunkel "
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High-Density Genomewide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel Loci
Steven E. Boyden,Louis M. Kunkel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012432
Abstract: Human lifespan is approximately 25% heritable, and genetic factors may be particularly important for achieving exceptional longevity. Accordingly, siblings of centenarians have a dramatically higher probability of reaching extreme old age than the general population.
Analysis of human sarcospan as a candidate gene for CFEOM1
Kristine F O'Brien, Elizabeth C Engle, Louis M Kunkel
BMC Genetics , 2001, DOI: 10.1186/1471-2156-2-3
Abstract: When tested by polymerase chain reaction, sarcospan sequence was not detected on yeast or bacterial artificial chromosomes from the CFEOM1 critical region. Sequencing of the sarcospan gene in CFEOM1 patients from 6 families revealed no mutations. Immunohistochemical studies of CFEOM1 extraocular muscles showed normal levels of sarcospan at the membrane. Finally, sarcospan was electronically mapped to bacterial artificial chromosomes that are considered to be outside of the CFEOM1 critical region.In this report we evaluate sarcospan as a candidate gene for CFEOM1. We have found that it is highly unlikely that sarcospan is involved in the pathogenesis of this disease. As of yet no sarcospan gene mutations have been found to cause muscular abnormalities.CFEOM1 is an autosomal dominant disorder that has been linked to the pericentromere of chromosome 12, flanked by marker D12S1584 on the p arm and D12S1668 on the q arm [1, 2]. The clinical phenotype consists of congenital, bilateral ptosis and external ophthalmoplegia, with the eyes partially or completely fixed in a hypotrophic or downward position. On autopsy, CFEOM1 patients appear to be lacking the superior division of cranial nerve III, which innervates the levator and superior rectus muscles [3]. Whether this disease is caused by a primary defect in the nerve or the muscle remains unclear. The disease was initially linked to an 8 centiMorgan region spanning the centromere of chromosome 12, and then further refined to a critical region of 3 cM [1, 2]. Yeast and bacterial artificial chromosome (YAC and BAC) contigs have been generated and a positional cloning approach to identify the CFEOM1 causative gene is ongoing.Sarcospan is a member of the dystrophin associated protein complex present in skeletal and extraocular muscle [4,5,6]. Sarcospan is most tightly associated with the transmembrane sarcoglycan subcomplex, mutation of which causes autosomal recessive limb girdle muscular dystrophy (LGMD2C-2F) [7,8,9,10,11].
Genomic organization and single-nucleotide polymorphism map of desmuslin, a novel intermediate filament protein on chromosome 15q26.3
Yuji Mizuno, Annibale A Puca, Kristine F O'Brien, Alan H Beggs, Louis M Kunkel
BMC Genetics , 2001, DOI: 10.1186/1471-2156-2-8
Abstract: The desmuslin gene was localized to chromosome 15q26.3 by electronic screening of the human DNA sequence database. Primer pairs were designed to amplify the 5 exons of the desmuslin gene in 11 overlapping DNA segments. The desmuslin gene was screened for mutations in 71 patients with various forms of myopathy for which there was no known cause. In this analysis, 10 common and 2 rare amino acid altering single-nucleotide polymorphisms were identified, all of which were seen in a control population of individuals thus making these unlikely causes of the phenotype. Interestingly, one of the single-nucleotide polymorphisms found in a patient resulted in a premature stop codon in the first exon. The nonsense mutation was also detected in the patient's unaffected father and one unaffected control; it was detected in 0.44% (2/454) of unrelated chromosomes and is therefore predicted to have a homozygous frequency of 0.002%.No causative mutations were found in the desmuslin gene. However, the single-nucleotide polymorphisms mapped in this study represent a well-mapped group that can be used for disequilibrium studies of this region of chromosome 15q26.3.Dystrophin and its associated proteins are thought to be involved in the anchoring of the muscle cell membrane to the extracellular matrix [1], and the absence of many of these proteins can lead to the phenotype of muscular dystrophy [2]. The dystrophin-associated protein complex (DAPC) consists of several subgroups of protein complexes, each associated either directly or indirectly with dystrophin. The sarcoglycans are four transmembrane proteins [3] that are organized by a fifth protein called sarcospan [4]. This complex is thought to be involved in signalling at the cell membrane [5]. A second subcomplex, known as the dystroglycan complex [6], interacts directly with dystrophin in the cytoplasm and laminin in the extracellular matrix, thus providing a structural link between the inside and the outside of the cell. A third
Detection of mutations in the dystrophin gene via automated DHPLC screening and direct sequencing
Richard R Bennett, Johan den Dunnen, Kristine F O'Brien, Basil T Darras, Louis M Kunkel
BMC Genetics , 2001, DOI: 10.1186/1471-2156-2-17
Abstract: Using denaturing high performance liquid chromatography (DHPLC) screening and direct sequencing, 86 PCR amplicons of genomic DNA from the dystrophin gene were screened for mutations in eight patients diagnosed with DMD who had tested negative for large DNA rearragements. Mutations likely to be disease-causative were found in six of the eight patients. All 86 amplicons from the two patients in whom no likely disease-causative mutations were found were completely sequenced and only polymorphisms were found.We have shown that it is now feasible for clinical laboratories to begin testing for both point mutations and large deletions/duplications in the dystrophin gene. The detection rate will rise from 65% to greater than 92% with only a moderate increase in cost.Dystrophinopathies are X-linked recessive diseases caused by primary dystrophin deficiency, and include: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), manifesting DMD/BMD carrier females, X-linked dilated cardiomyopathy, isolated quadriceps myopathy, muscle cramps with myoglobinuria and asymptomatic elevation of muscle enzymes [1].The DMD gene spans 2.4 million base pairs of genomic DNA on the X chromosome and its 14 kb transcript encodes a full-length protein (dystrophin) of 427 kiloDaltons. Dystrophin is a sarcolemmal protein that through its interaction with many other proteins participates in the linkage of the extracellular matrix to the cytoplasmic cytoskeleton [2-4]. Mutations in this gene result in DMD, BMD or other dystrophinopathy. A major consequence of the dystrophin gene's large genomic size is a high rate of mutation; close to 30% of cases prove to be spontaneous mutations[5]. Approximately 60% of mutations causing DMD are deletions of large segments of the gene usually including one or more exons [6-8]. Approximately 5% of mutations are duplications of large segments of the gene[8]. Large deletions and duplications are detected using multiplexed PCR primers to amplify a subse
Transcriptome-scale similarities between mouse and human skeletal muscles with normal and myopathic phenotypes
Alvin T Kho, Peter B Kang, Isaac S Kohane, Louis M Kunkel
BMC Musculoskeletal Disorders , 2006, DOI: 10.1186/1471-2474-7-23
Abstract: Orthologous (whole, sub-) transcriptome profiles were compared among four mouse-human transcriptome datasets: (M) six muscle groups obtained from three mouse strains (wildtype, mdx, mdx5cv); (H1) biopsied human quadriceps from controls and Duchenne muscular dystrophy patients; (H2) four different control human muscle types obtained at autopsy; and (H3) 12 different control human tissues (ten non-muscle).Of the six mouse muscles examined, mouse soleus bore the greatest molecular similarities to human skeletal muscles, independent of the latters' anatomic location/muscle type, disease state, age and sampling method (autopsy versus biopsy). Significant similarity to any one mouse muscle group was not observed for non-muscle human tissues (dataset H3), indicating this finding to be muscle specific.This observation may be partly explained by the higher type I fiber content of soleus relative to the other mouse muscles sampled.Animal models of human diseases are used extensively to study basic disease processes and test potential therapies. Even though these proxies have ethical and practical advantages, they generally do not completely recapitulate the human disease phenotype. For example, mdx and mdx5cv mice have mutations in the dystrophin gene mirroring the genetic defect of human Duchenne muscular dystrophy (DMD) [1-4], yet they experience milder muscle degeneration than DMD patients [3,5,6]. Consequently, extrapolating findings from a mouse model to human disease can have limitations.Different skeletal muscle groups are dissimilarly affected in muscular dystrophies, suggesting inherent molecular and physiological differences among muscle groups. This raises the question of whether one type of mouse muscle more accurately represents particular (myopathic) characteristics in a given human muscle type than another. Based on gross histology, skeletal muscles differ in at least four parameters: bulk, length, fiber architecture and fiber type proportions. It is not immedi
Beta-synemin expression in cardiotoxin-injected rat skeletal muscle
Yuji Mizuno, Jeffrey R Guyon, Akiko Ishii, Sachiko Hoshino, Norio Ohkoshi, Akira Tamaoka, Koichi Okamoto, Louis M Kunkel
BMC Musculoskeletal Disorders , 2007, DOI: 10.1186/1471-2474-8-40
Abstract: The two α-dystrobrevin isoforms (-1 and -2) and β-synemin were localized in regenerating rat tibialis anterior muscle using immunoprecipitation, immunohistochemical and immunoblot analyses. Immunoprecipitation and co-localization studies for α-dystrobrevin and β-synemin were performed in regenerating muscle following cardiotoxin injection. Protein expression was then compared to that of developing rat muscle using immunoblot analysis.With an anti-α-dystrobrevin antibody, β-synemin co-immunoprecipitated with α-dystrobrevin whereas with an anti-β-synemin antibody, α-dystrobrevin-1 (rather than the -2 isoform) preferentially co-immunoprecipitated with β-synemin. Immunohistochemical experiments show that β-synemin and α-dystrobrevin co-localize in rat skeletal muscle. In regenerating muscle, β-synemin is first expressed at the sarcolemma and in the cytoplasm at day 5 following cardiotoxin injection. Similarly, β-synemin and α-dystrobrevin-1 are detected by immunoblot analysis as weak bands by day 7. In contrast, immunoblot analysis shows that α-dystrobrevin-2 is expressed as early as 1 day post-injection in regenerating muscle. These results are similar to that of developing muscle. For example, in embryonic rats, immunoblot analysis shows that β-synemin and α-dystrobevin-1 are weakly expressed in developing lower limb muscle at 5 days post-birth, while α-dystrobrevin-2 is detectable before birth in 20-day post-fertilization embryos.Our results clearly show that β-synemin expression correlates with that of α-dystrobrevin-1, suggesting that β-synemin preferentially functions with α-dystrobrevin-1 in vivo and that these proteins are likely to function coordinately to play a vital role in developing and regenerating muscle.Synemin is a muscle intermediate filament protein that was originally identified in chickens [1]. Recently, human α- and β-synemin orthologues have been cloned [2,3], the latter of which was previously termed human desmuslin [2]. Both human synemin isofo
Reproducibility of gene expression across generations of Affymetrix microarrays
Ashish Nimgaonkar, Despina Sanoudou, Atul J Butte, Judith N Haslett, Louis M Kunkel, Alan H Beggs, Isaac S Kohane
BMC Bioinformatics , 2003, DOI: 10.1186/1471-2105-4-27
Abstract: Correlation coefficients were computed for gene expression values across chip generations based on different measures of similarity. Comparing the absolute calls assigned to the individual probe sets across the generations found them to be largely unchanged.We show that experimental replicates are highly reproducible, but that reproducibility across generations depends on the degree of similarity of the probe sets and the expression level of the corresponding transcript.Expression microarrays provide a vehicle for exploring the gene expression in a manner that is rapid, sensitive, systematic and comprehensive [1-6]. Thousands of genes can now be studied simultaneously without the need of an a priori candidate gene list. In order to keep up with advances in genome sequencing, the number and composition of representative gene sequences are frequently updated and probe sets representing newly discovered expressed sequences are added on commercial microarrays. Furthermore, existing probe sets are revised because probe sequences once thought to be unique for a single gene are occasionally found to be less specific. This leads to the question of whether results from newer microarray generations are comparable to those of previous generations. The cost, time and irreplaceable nature of some of the samples used for microarray analysis require that a method to compare data from different generations be developed.Although Affymetrix Chips can each measure the expression of over 12,000 genes and ESTs, the true transcript level is confounded by a substantial amount of noise and variability induced by both the large number of observations and the wide range of gene expression values [7]. Microarrays are sensitive to noise from many sources including the manufacturing process and the experimental (RNA isolation, labeling, hybridization, staining, washing and scanning) processes. Even within the same generation of chips and for replicates of single tissue samples, there may be sub
The Co-Morbidity Burden of Children and Young Adults with Autism Spectrum Disorders
Isaac S. Kohane, Andrew McMurry, Griffin Weber, Douglas MacFadden, Leonard Rappaport, Louis Kunkel, Jonathan Bickel, Nich Wattanasin, Sarah Spence, Shawn Murphy, Susanne Churchill
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033224
Abstract: Objectives Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults. Study Design A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18–34 years) individuals with ASD was compared. Results 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58–14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89–2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13–0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72–6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41–10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3–0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26–0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79–1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI ?0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0–17 vs 18–34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly. Conclusions The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.
Zebrafish orthologs of human muscular dystrophy genes
Leta S Steffen, Jeffrey R Guyon, Emily D Vogel, Rosanna Beltre, Timothy J Pusack, Yi Zhou, Leonard I Zon, Louis M Kunkel
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-79
Abstract: Zebrafish sequence databases were queried for transcripts orthologous to human dystrophy-causing genes, identifying transcripts for 28 out of 29 genes of interest. In addition, the genomic locations of all 29 genes have been found, allowing rapid candidate gene discovery during genetic mapping of zebrafish dystrophy mutants. 19 genes show conservation of syntenic relationships with humans and at least two genes appear to be duplicated in zebrafish. Significant sequence coverage on one or more BAC clone(s) was also identified for 24 of the genes to provide better local sequence information and easy updating of genomic locations as the zebrafish genome assembly continues to evolve.This resource supports zebrafish as a dystrophy model, suggesting maintenance of all known dystrophy-associated genes in the zebrafish genome. Coupled with the ability to conduct genetic screens and small molecule screens, zebrafish are thus an attractive model organism for isolating new dystrophy-causing genes/pathways and for use in high-throughput therapeutic discovery.Muscular dystrophies are a heterogeneous group of genetic disorders characterized by loss of muscle strength and integrity. Common pathological hallmarks of the mammalian muscular dystrophies include the presence of necrotic muscle fibers, fiber size variation, centralized nuclei indicating fiber regeneration, inflammatory infiltrates, and replacement of muscle fibers by fat and connective tissue to varying degrees. However, muscular dystrophies differ in their age of onset, severity, the muscle groups affected, additional non-muscle phenotypes (such as reduced average IQ) and the genetic mode of inheritance (reviewed in [1]).To date, 31 distinct muscular dystrophies have been described and 25 distinct genes have been causatively linked to these muscular dystophies [2]. The most common, Duchenne Muscular Dystrophy (DMD), accounts for the majority of dystrophy patients. DMD affects 1 in 3500 males and typically results in de
Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE
Steven E Boyden, Anna R Duncan, Elicia A Estrella, Hart GW Lidov, Lane J Mahoney, Jonathan S Katz, Louis M Kunkel, Peter B Kang
BMC Medical Genetics , 2011, DOI: 10.1186/1471-2350-12-87
Abstract: We performed high-density genomewide linkage analysis and mutation screening of candidate genes to identify the genetic defect in the family. Preserved clinical biopsy material was reviewed to confirm the diagnosis, and reverse transcriptase PCR was used to determine the molecular effect of a splice site mutation.The linkage scan excluded the majority of known myopathy genes, but one linkage peak included the gene GNE, in which mutations cause autosomal recessive hereditary inclusion body myopathy type 2 (HIBM2). Muscle biopsy tissue from a patient showed myopathic features, including small basophilic fibers with vacuoles. Sequence analysis of GNE revealed affected individuals were compound heterozygous for a novel mutation in the 5' splice donor site of intron 10 (c.1816+5G>A) and a previously reported missense mutation (c.2086G>A, p.V696M), confirming the diagnosis as HIBM2. The splice site mutation correlated with exclusion of exon 10 from the transcript, which is predicted to produce an in-frame deletion (p.G545_D605del) of 61 amino acids in the kinase domain of the GNE protein. The father of the proband was heterozygous for the splice site mutation and exhibited mild distal weakness late in life.Our study expands on the extensive allelic heterogeneity of HIBM2 and demonstrates the value of linkage analysis in resolving ambiguous clinical findings to achieve a molecular diagnosis.Hereditary inclusion body myopathy (HIBM) is characterized by slowly progressive muscle weakness, preferentially affecting the tibialis anterior and usually sparing the quadriceps. Onset is generally between the ages of 20 and 40 and serum creatine kinase (CK) levels are normal or minimally elevated. Histological features include the presence in myofibers of vacuoles rimmed with basophilic granular material, as well as cytoplasmic filamentous inclusions on electron microscopy [1]. Rimmed vacuoles are a defining characteristic of HIBM, but are also observed less consistently in other mus
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