Jin Yan

Beckman Research Institute, Duarte, California, United States

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Publications (21)60 Total impact

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    ABSTRACT: In a large Scottish pedigree, a balanced translocation t (1;11)(q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family with schizophrenia, but subsequently found in two controls. Herein, we test one hypothesis utilizing a large scale case-control mutation analysis: uncommon DISC1 variants are associated with high risk for bipolar spectrum disorder. We have analyzed the regions of likely functional significance in the DISC1 gene in 504 patients with bipolar spectrum disorder and 576 ethnically similar controls. Five patients were heterozygous for ultra-rare protein structural variants not found in the 576 controls (p=0.02, one-sided Fisher's exact test) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. In our sample, ultra-rare (private) protein structural variants in DISC1 are associated with an estimated attributable risk of about 0.5% in bipolar spectrum disorder. These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (<3-fold odds ratio). The data illustrate how low/moderate risk haplotypes that might be found by the HapMap project can be followed up by resequencing to identify protein structural variants with high risk, low frequency and of potential clinical utility.
    Neuroscience Letters 12/2010; 486(3):136-40. · 2.03 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are 21-25-nucleotide-long, noncoding RNAs that are involved in translational regulation. Most miRNAs derive from a two-step sequential processing: the generation of pre-miRNA from pri-miRNA by the Drosha/DGCR8 complex in the nucleus, and the generation of mature miRNAs from pre-miRNAs by the Dicer/TRBP complex in the cytoplasm. Sequence variation around the processing sites, and sequence variations in the mature miRNA, especially the seed sequence, may have profound affects on miRNA biogenesis and function. In the context of analyzing the roles of miRNAs in Schizophrenia and Autism, we defined at least 24 human X-linked miRNA variants. Functional assays were developed and performed on these variants. In this study we investigate the affects of single nucleotide polymorphisms (SNPs) on the generation of mature miRNAs and their function, and report that naturally occurring SNPs can impair or enhance miRNA processing as well as alter the sites of processing. Since miRNAs are small functional units, single base changes in both the precursor elements as well as the mature miRNA sequence may drive the evolution of new microRNAs by altering their biological function. Finally, the miRNAs examined in this study are X-linked, suggesting that the mutant alleles could be determinants in the etiology of diseases.
    RNA 08/2009; 15(9):1640-51. · 5.09 Impact Factor
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    ABSTRACT: Schizophrenia is a severe disabling brain disease affecting about 1% of the population. Individual microRNAs (miRNAs) affect moderate downregulation of gene expression. In addition, components required for miRNA processing and/or function have also been implicated in X-linked mental retardation, neurological and neoplastic diseases, pointing to the wide ranging involvement of miRNAs in disease. To explore the role of miRNAs in schizophrenia, 59 microRNA genes on the X-chromosome were amplified and sequenced in males with (193) and without (191) schizophrenia spectrum disorders to test the hypothesis that ultra-rare mutations in microRNA collectively contribute to the risk of schizophrenia. Here we provide the first association of microRNA gene dysfunction with schizophrenia. Eight ultra-rare variants in the precursor or mature miRNA were identified in eight distinct miRNA genes in 4% of analyzed males with schizophrenia. One ultra-rare variant was identified in a control sample (with a history of depression) (8/193 versus 1/191, p = 0.02 by one-sided Fisher's exact test, odds ratio = 8.2). These variants were not found in an additional 7,197 control X-chromosomes. Functional analyses of ectopically expressed copies of the variant miRNA precursors demonstrate loss of function, gain of function or altered expression levels. While confirmation is required, this study suggests that microRNA mutations can contribute to schizophrenia.
    PLoS ONE 02/2009; 4(7):e6121. · 3.73 Impact Factor
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    ABSTRACT: Frameshift and missense mutations in the X-linked neuroligin 4 (NLGN4, MIM# 300427) and neuroligin 3 (NLGN3, MIM# 300336) genes have been identified in patients with autism, Asperger syndrome and mental retardation. We hypothesize that sequence variants in NLGN4Y are associated with autism or mental retardation. The coding sequences and splice junctions of the NLGN4Y gene were analyzed in 335 male samples (290 with autism and 45 with mental retardation). A total of 1.1 Mb of genomic DNA was sequenced. One missense variant, p.I679V, was identified in a patient with autism, as well as his father with learning disabilities. The I679 residue is highly conserved in three members of the neuroligin family. The absence of p.I679V in 2986 control Y chromosomes and the high similarity of NLGN4 and NLGN4Y are consistent with the hypothesis that p.I679V contributes to the etiology of autism. The presence of only one structural variant in our population of 335 males with autism/mental retardation, the unavailability of significant family cosegregation and an absence of functional assays are, however, important limitations of this study.
    Psychiatric genetics 08/2008; 18(4):204-7. · 2.33 Impact Factor
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    ABSTRACT: Neurexins are presynaptic membrane cell-adhesion molecules which bind to neuroligins, a family of proteins that are associated with autism. To explore the possibility that structural variants in the neurexin alpha genes predispose to autism, the coding regions and associated splice junctions of the neurexin 1alpha gene were sequenced in 116 Caucasian patients with autism and 192 Caucasian controls. Five ultra-rare structural variants including a predicted splicing mutation were found in patients with autism and absent in 10,000 control alleles. Only one ultra-rare structural variant was found in controls (5/116 vs. 1/192; P=0.03, Fisher's exact test, one-sided). In the context of all available data, the ultra-rare structural variants of the neurexin 1alpha gene are consistent with mutations predisposing to autism.
    Neuroscience Letters 07/2008; 438(3):368-70. · 2.03 Impact Factor
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    ABSTRACT: In this work we explored the role of the 3'UTR of the MECP2 gene in patients with clinical diagnosis of RTT and mental retardation; focusing on regions of the 3'UTR with almost 100% conservation at the nucleotide level among mouse and human. By mutation scanning (DOVAM-S technique) the MECP2 3'UTR of a total of 66 affected females were studied. Five 3'UTR variants in the MECP2 were found (c.1461+9G>A, c.1461+98insA, c.2595G>A, c.9961C>G and c.9964delC) in our group of patients. None of the variants found is located in putative protein-binding sites nor predicted to have a pathogenic role. Our data suggest that mutations in this region do not account for a large proportion of the RTT cases without a genetic explanation.
    Disease markers 01/2008; 24(6):319-24. · 2.14 Impact Factor
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    ABSTRACT: Although DOVAM-S (detection of virtually all mutations-SSCP) in effect detects all mutations and is less costly than direct sequencing, the technique currently requires the use of radioactivity. F-DOVAM-S (fluorescent DOVAM-S) was developed to replace the isotopic label with fluorescence and to increase throughput via dye color multiplexing. As proof of principle, two multitemperature slab gel electrophoresis conditions were evaluated through the blinded analysis of mutations in the factor IX (FIX) genes of 88 hemophilia B (HB) patients and 7 wild-type controls. Using only two conditions, it was determined that F-DOVAM-S had a detection sensitivity of 97%. It is anticipated that when three or four optimized conditions are employed, F-DOVAM-S will detect all mutations. Three patient samples were multiplexed per well using three different fluorescent dyes (6FAM, VIC, and NED), demonstrating that it is possible to analyze up to 44 kb of diploid, color-coded amplification product per gel lane. This value corresponds to a throughput of approximately 4 Mb of DNA analyzed per 96-well gel, which is approximately triple that of conventional radiolabeled DOVAM-S. Throughput is further enhanced by the rapidity at which the fluorescent signal can be captured and the resultant multicolor chromatograms analyzed. Given these data, F-DOVAM-S has the potential to be a particularly powerful technology for clinical diagnosis because it allows the mutation analysis of multiple patients to be performed within 24h.
    Analytical Biochemistry 10/2007; 368(2):250-7. · 2.58 Impact Factor
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    ABSTRACT: Mutations in the coding sequence of the methyl-CpG-binding protein 2 gene (MECP2), which cause Rett syndrome (RTT), have been found in male and female autistic subjects without, however, a causal relation having unequivocally been established. In this study, the MECP2 gene was scanned in a Portuguese autistic population, hypothesizing that the phenotypic spectrum of mutations extends beyond the traditional diagnosis of RTT and X-linked mental retardation, leading to a non-lethal phenotype in male autistic patients. The coding region, exon-intron boundaries, and the whole 3'UTR were scanned in 172 patients and 143 controls, by Detection of Virtually All Mutations-SSCP (DOVAM-S). Exon 1 was sequenced in 103 patients. We report 15 novel variants, not found in controls: one missense, two intronic, and 12 in the 3'UTR (seven in conserved nucleotides). The novel missense change, c.617G > C (p.G206A), was present in one autistic male with severe mental retardation and absence of language, and segregates in his maternal family. This change is located in a highly conserved residue within a region involved in an alternative transcriptional repression pathway, and likely alters the secondary structure of the MeCP2 protein. It is therefore plausible that it leads to a functional modification of MeCP2. MECP2 mRNA levels measured in four patients with 3'UTR conserved changes were below the control range, suggesting an alteration in the stability of the transcripts. Our results suggest that MECP2 can play a role in autism etiology, although very rarely, supporting the notion that MECP2 mutations underlie several neurodevelopmental disorders.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2007; 144B(4):475-83. · 3.23 Impact Factor
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    ABSTRACT: For epidemiological and diagnostic applications, detection of virtually all mutations is desired. Herein, blinded analyses of DOVAM-S (Detection Of Virtually All Mutations-SSCP), a robotically enhanced multiplex SSCP method, demonstrate that all of 525 mutations (391 unique) are detected by the method. In addition, the costs of DOVAM-S, gel-based fluorescent sequencing and capillary-based fluorescent sequencing are compared. The relative cost effectiveness of gel-based and capillary-based sequence analysis depends on throughput and whether depreciation and service are considered. DOVAM-S reduces the cost of candidate gene analyses relative to brute force sequencing by about threefold.
    Genetic Testing 02/2007; 11(3):235-40. · 1.17 Impact Factor
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    ABSTRACT: Neuroligins are postsynaptic membrane cell-adhesion molecules which bind to beta-neurexins, a family of proteins that act as neuronal cell surface receptors. To explore the possibility that structural variants in the beta-neurexin genes predispose to autism, the coding regions and associated splice junctions of three beta-neurexin genes were scanned with detection of virtually all mutations-SSCP (DOVAM-S) in 72 Caucasian patients with autism. In addition, segments of the neurexin 1beta gene were sequenced in 131 additional Caucasian and 61 Afro-American patients with autism from South Carolina and the Midwest. Two putative missense structural variants were identified in the neurexin 1beta gene in four Caucasian patients with autism and not in 535 healthy Caucasian controls (4/203 vs. 0/535, P=0.0056). Initial family data suggest that incomplete penetrance may occur. In addition, no structural variant was found in the neurexin 2beta gene and the neurexin 3beta gene. In the context of all available data, we conclude that mutations of the neurexin 1beta gene may contribute to autism susceptibility.
    Neuroscience Letters 12/2006; 409(1):10-3. · 2.03 Impact Factor
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    ABSTRACT: Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.
    Human Mutation 10/2005; 26(4):303-7. · 5.21 Impact Factor
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    ABSTRACT: Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20-24 patients with bipolar disorder (BPD), attention-deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARbeta, RARgamma, and RXRgamma genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2005; 133B(1):50-3. · 3.23 Impact Factor
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    ABSTRACT: An analysis of mutations was performed in 141 Duchenne muscular dystrophy (DMD) patients previously found to be negative for large deletions by standard multiplex PCR assays. Comprehensive mutation scanning of all coding exons, adjacent intronic splice regions, and promoter sequences was performed by DOVAM-S, a robotically enhanced, high throughput method that detects essentially all point mutations. Samples negative for point mutations were further analyzed for duplications by multiplex amplifiable probe hybridization (MAPH). Presumptive causative mutations were detected in 90% of the patients (70% protein truncating point mutations, 13% duplications, and 7% deletions not detected by the standard multiplex screening method). A total of 40 of the mutations are putatively novel. Most duplications involve multiple exons with an average and median size of about 160 and 153 kb, respectively. This is the first analysis of the absolute and relative rates of point mutations in the dystrophin gene. Relative to microdeletions (0.68 x 10(-9) per bp per generation), transitions at CpG dinucleotides are enhanced 150-fold while complex indels, the least common mutation type, are less frequent than microdeletions by a factor of five. The frequency of microdeletions and microinsertions at mononucleotide repeats increases exponentially with length. When compared to the well-studied human factor IX gene (F9), the results are similar, with two exceptions: a hotspot of mutation in the dystrophin gene (c.8713C>T/p.R2905X) at a CpG dinucleotide and an altered size distribution of microdeletions. The hotspot reflects a difference in the underlying pattern of mutation, while the altered size distribution of microdeletions reflects certain abundant sequence motifs within the dystrophin coding sequence (relative to factor IX).
    Human Mutation 02/2005; 25(2):177-88. · 5.21 Impact Factor
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    ABSTRACT: Intriguing parallels have been noted previously between the biology of Vitamin D and the epidemiology of schizophrenia. We have scanned the Vitamin D receptor (VDR) gene by DOVAM-S (Detection of Virtually All Mutations-SSCP), a robotically enhanced multiplexed scanning method. In total, 100 patients with schizophrenia (86 Caucasians and 14 African-Americans) were scanned. In addition, pilot experiments were performed in patients with bipolar disorder (BPD) (24), autism (24), attention deficit hyperactivity disorder (ADHD) (24), and alcoholism (20). A total of 762 kb of the VDR genomic sequence was scanned. R208N and V339I were each found in one African-American patient, while absent in 35 African-American controls without schizophrenia (2/14 versus 0/35, P=0.08). Within the power of the study (> or =1.6-fold relative risk), the common M1T variant is not associated with schizophrenia. In the 92 scanned patients with other psychiatric diseases, R173S was found in a single patient with bipolar disorder. In conclusion, we describe three novel structural variants of the Vitamin D receptor. Further study is required to clarify their role, if any, in psychiatric disease.
    Neuroscience Letters 01/2005; 380(1-2):37-41. · 2.03 Impact Factor
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    ABSTRACT: Well-characterized epidemiological resources are generated with great effort, yet associated patient DNA samples can be limiting. The efficacy of the whole genome amplification (WGA) method, termed multiple displacement amplification (MDA), was assessed for detecting heterozygous sequence variants, mutation scanning, and PCR for challenging segments. Fifteen common polymorphisms from 10 genes located on 8 chromosomes were genotyped by direct sequencing of 300 PCR products from 115 high-quality MDA-amplified DNA samples extracted by different methods. The GC content of these analyzed segments ranges from 30% to 69%. Genotyping results demonstrate 100% accuracy. For heterozygotes, the relative intensity of peaks generated by the two alleles is highly similar for genomic and MDA-amplified genomic DNA, independent of GC content. In contrast, one of four heterozygous loci was mistyped when lower quality MDA-amplified DNA samples were used. The results of single-stranded conformation polymorphism (SSCP)-type of mutation scanningfor seven MDA-amplified DNA samples in four genes were concordant with the genomic DNA samples. PCR on MDA-amplified DNA was routinely successful for challenging 10- and 12-kb segments with GC content ranging from 30% to 80%, demonstrating that rather long segments, which are difficult to amplify with PCR, are amplified well with MDA. These results suggest that MDA is an effective method of WGA with utility in molecular epidemiology. Quality control of the MDA-amplified DNA is critical for high performance.
    BioTechniques 08/2004; 37(1):136-8, 140-3. · 2.40 Impact Factor
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    ABSTRACT: Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2004; 128B(1):50-3. · 3.23 Impact Factor
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    ABSTRACT: Sex steroids exert potent effects on mood and mental state in humans. They may contribute to the risk of psychiatric disorders. To investigate this hypothesis, coding and splice junction sequences of the androgen receptor gene were scanned in genomic DNA samples to search for variants affecting protein structure and expression (VAPSEs). Ninety-six schizophrenics, along with pilot samples of patients with bipolar disorder, attention-deficit hyperactivity disorder, alcoholism and autism were analyzed with DOVAM-S, a robotically enhanced, optimized form of single-strand conformation polymorphism analysis. A total of 669 kb of genomic sequence was analyzed. Two VAPSEs were identified: R726L was found in one of 17 scanned alcoholics, and P516S, a novel VAPSE, was identified in one of three phobia patients. There were no length trends of the CAG triplets associated with schizophrenia. R726L and P516S occur at highly conserved amino acids. Further study is required to assess whether these VAPSEs contribute to the risk of alcoholism or phobia or other diseases.
    Psychiatric Genetics 04/2004; 14(1):57-60. · 2.37 Impact Factor
  • Human Mutation 03/2004; 23(2):203-4. · 5.21 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that germline missense mutations in the ATM gene predispose to breast cancer. To investigate the potential role of somatic ATM mutations in the tumorigenesis of breast cancer, the ATM gene was scanned in 58 mammary carcinomas using DOVAM-S (detection of virtually all mutations-SSCP [single-strand conformation polymorphism]), a robotically enhanced, highly redundant form of SSCP that detects virtually all mutations. A total of 1.65 megabases of tumor DNA sequence was scanned and 16 structural variants were identified, including one novel nonsense mutation, four novel missense mutations, and a common missense change in African-Americans. Sequencing from microdissected normal cells reveals that all variants were present in the germline. Thus, the ATM gene may be similar to the BRCA1/BRCA2 genes in that germline mutations are important in cancer predisposition, but somatic mutations are seldom present in tumors. Loss of heterozygosity (LOH) is common in these tumors, but ATM missense mutations occur with similar frequencies when LOH is present or absent (P=0.73). If germline ATM missense mutations predispose to breast cancer, the unmasking of a recessive missense allele by LOH does not seem to be a critical step in breast neoplasia.
    Cancer Genetics and Cytogenetics 10/2003; 145(2):179-82. · 1.93 Impact Factor
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    ABSTRACT: Dilated cardiomyopathy (DCM) is the major indication for heart transplantation. Approximately 30% of all DCM is thought to be inherited, while 70% is sporadic. Mutations in the dystrophin gene have been associated with the uncommon X-linked form of DCM. We hypothesized that missense mutations and other less severe mutations of the dystrophin gene might predispose to the common form of sporadic DCM. To test this hypothesis, 22kb of genomic dystrophin DNA was scanned with DOVAM-S in each of the 22 patients with sporadic DCM, including all 79 coding sequences and splice junctions, as well as six alternative exon 1 dystrophin isoforms (484kb, total). Three putative new mutations (IVS5+1 G>T, K18N, and F3228L) and seven polymorphisms were identified. The splice site mutation IVS5+1 is predicted to cause skipping of exon 5, which is within a region containing an actin binding site. The missense mutations occur at amino acids that display substantial evolutionary conservation. Screening of 236 control individuals failed to identify these three mutations. The three patients with putative mutations had CK-MM (creatine kinase, skeletal muscle) levels greater than 250 units while the 14 patients without mutations for which CK-MM were available had values ranging from 20 to 200. The first comprehensive mutation scanning of the exons and splice junctions of the dystrophin gene in patients with sporadic DCM presents the evidence that point mutations are associated with sporadic DCM without clinical evidence of skeletal myopathy. It may be prudent to measure CK-MM in all patients with dilated cardiomyopathy to identify candidates at high risk for dystrophin mutations.
    Molecular Genetics and Metabolism 01/2002; 77(1-2):119-26. · 2.83 Impact Factor

Publication Stats

713 Citations
60.00 Total Impact Points

Institutions

  • 2002–2010
    • Beckman Research Institute
      Duarte, California, United States
  • 2001–2009
    • City of Hope National Medical Center
      • Department of Molecular and Cellular Biology
      Duarte, California, United States
  • 2005
    • Duke University Medical Center
      • Department of Medicine
      Durham, NC, United States