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1.
Nature ; 618(7963): 144-150, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37165196

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.


Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Carcinoma, Pancreatic Ductal , Lymphocyte Activation , Pancreatic Neoplasms , T-Lymphocytes , Humans , Adjuvants, Immunologic/therapeutic use , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/therapy , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Immunotherapy , Lymphocyte Activation/immunology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , T-Lymphocytes/cytology , T-Lymphocytes/immunology , mRNA Vaccines
2.
Nature ; 606(7913): 389-395, 2022 06.
Article in English | MEDLINE | ID: mdl-35589842

ABSTRACT

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens4,5, and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.


Subject(s)
Antigens, Neoplasm , Cancer Survivors , Pancreatic Neoplasms , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , T-Lymphocytes/immunology , Tumor Escape/immunology
3.
Am J Med Genet B Neuropsychiatr Genet ; 171B(3): 333-41, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26823146

ABSTRACT

There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn(2+) finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant-encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein-segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders.


Subject(s)
DNA-Binding Proteins/genetics , Depressive Disorder, Major/genetics , Family , Polymorphism, Single Nucleotide/genetics , Transcription Factors, General/genetics , Transcription Factors/genetics , Age of Onset , Alleles , Exome/genetics , Female , Humans , Male , Mutation/genetics , Pedigree , Sequence Analysis, DNA
5.
Brain ; 135(Pt 9): 2642-60, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22961544

ABSTRACT

Mutations in FLNC cause two distinct types of myopathy. Disease associated with mutations in filamin C rod domain leading to expression of a toxic protein presents with progressive proximal muscle weakness and shows focal destructive lesions of polymorphous aggregates containing desmin, myotilin and other proteins in the affected myofibres; these features correspond to the profile of myofibrillar myopathy. The second variant associated with mutations in the actin-binding domain of filamin C is characterized by weakness of distal muscles and morphologically by non-specific myopathic features. A frameshift mutation in the filamin C rod domain causing haploinsufficiency was also found responsible for distal myopathy with some myofibrillar changes but no protein aggregation typical of myofibrillar myopathies. Controversial data accumulating in the literature require re-evaluation and comparative analysis of phenotypes associated with the position of the FLNC mutation and investigation of the underlying disease mechanisms. This is relevant and necessary for the refinement of diagnostic criteria and developing therapeutic approaches. We identified a p.W2710X mutation in families originating from ethnically diverse populations and re-evaluated a family with a p.V930_T933del mutation. Analysis of the expanded database allows us to refine clinical and myopathological characteristics of myofibrillar myopathy caused by mutations in the rod domain of filamin C. Biophysical and biochemical studies indicate that certain pathogenic mutations in FLNC cause protein misfolding, which triggers aggregation of the mutant filamin C protein and subsequently involves several other proteins. Immunofluorescence analyses using markers for the ubiquitin-proteasome system and autophagy reveal that the affected muscle fibres react to protein aggregate formation with a highly increased expression of chaperones and proteins involved in proteasomal protein degradation and autophagy. However, there is a noticeably diminished efficiency of both the ubiquitin-proteasome system and autophagy that impairs the muscle capacity to prevent the formation or mediate the degradation of aggregates. Transfection studies of cultured muscle cells imitate events observed in the patient's affected muscle and therefore provide a helpful model for testing future therapeutic strategies.


Subject(s)
Contractile Proteins/metabolism , Microfilament Proteins/metabolism , Muscle, Skeletal/metabolism , Muscular Dystrophies/metabolism , Mutation , Phenotype , Actins/metabolism , Adult , Contractile Proteins/genetics , Disease Progression , Female , Filamins , Heat-Shock Proteins/metabolism , Humans , Male , Microfilament Proteins/genetics , Middle Aged , Muscle, Skeletal/pathology , Muscular Dystrophies/genetics , Muscular Dystrophies/pathology , Pedigree , Protein Binding , Proteolysis , Ubiquitination
6.
Muscle Nerve ; 46(2): 275-82, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22806379

ABSTRACT

INTRODUCTION: Mutations in the gene that encodes filamin C, FLNC, represent a rare cause of a distinctive type of myofibrillar myopathy (MFM). METHODS: We investigated an Italian patient by means of muscle biopsy, muscle and brain imaging and molecular analysis of MFM genes. RESULTS: The patient harbored a novel 7256C>T, p.Thr2419Met mutation in exon 44 of FLNC. Clinical, pathological and muscle MRI findings were similar to the previously described filaminopathy cases. This patient had, in addition, cerebellar ataxia with atrophy of cerebellum and vermis evident on brain MRI scan. Extensive screening failed to establish a cause of cerebellar atrophy. CONCLUSIONS: We report an Italian filaminopathy patient, with a novel mutation in a highly conserved region. This case raises the possibility that the disease spectrum caused by FLNC may include cerebellar dysfunction.


Subject(s)
Contractile Proteins/genetics , Microfilament Proteins/genetics , Muscular Dystrophies/genetics , Spinocerebellar Degenerations/genetics , Aged , Filamins , Humans , Male , Muscle, Skeletal/pathology , Muscular Dystrophies/complications , Muscular Dystrophies/pathology , Spinocerebellar Degenerations/complications , Spinocerebellar Degenerations/pathology
7.
Eur Neurol ; 68(5): 279-86, 2012.
Article in English | MEDLINE | ID: mdl-23051780

ABSTRACT

BACKGROUND: Most of the previously described pathogenic mutations in desmin are located in highly conserved α-helical domains that play an important role in intermediate filament assembly. The role of the C-terminus non-α-helical 'tail' domain is much less investigated and until recently mutations in this domain have been implicated in only a few patients. The majority of reported desminopathy cases caused by the tail mutations were sporadic, creating a representation bias regarding the disease frequency and phenotypic characteristics. METHODS: We performed detailed genotype-phenotype analysis of autosomal dominant desminopathy associated with tail domain mutations in a four-generation autosomal dominant family with 16 members affected by a progressive cardiac and/or skeletal myopathy caused by a c.1346A>C (p.Lys449Thr) mutation located in the tail domain of desmin. RESULTS: Phenotypic features in patients with tail domain mutations are similar to those in patients with mutations localized in the 1B and 2B α-helical domains. CONCLUSION: We recommend that the tail domain is searched for mutations as intensely as desmin coil domains which until recently were considered to be more 'functional'.


Subject(s)
Desmin/genetics , Intermediate Filaments/pathology , Muscular Diseases/genetics , Mutation/genetics , Adult , Aged , Desmin/metabolism , Female , Humans , Intermediate Filaments/genetics , Intermediate Filaments/ultrastructure , Male , Middle Aged , Muscular Diseases/diagnosis , Muscular Diseases/physiopathology , Pedigree
8.
Muscle Nerve ; 42(6): 901-7, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21104864

ABSTRACT

Nemaline myopathy (NEM) is one of the most common congenital myopathies. A unique subtype, NEM6, maps to chromosome 15q21-q23 in two pedigrees, but the causative gene has not been determined. We conducted clinical examination and myopathological studies in a new NEM family. Genotyping and gene screening were accomplished by searching known and 18 new candidate genes. The disease started in childhood by affecting proximal and distal muscles and causing slowness of movements. Muscle biopsies showed numerous nemaline rods and core-like formations. Suggestive linkage to chromosome 15q22-q23 was established. Genes known to be mutated in NEM or core-rod myopathy were screened and excluded. No pathogenic mutations were identified in other candidate genes. The disease in this Spanish family was classified as NEM6. It is phenotypically similar and probably allelic to the two previously reported NEM6 pedigrees. Further studies of these families will lead to the identification of the NEM6 gene.


Subject(s)
Muscle, Skeletal/pathology , Adult , Female , Genotype , Humans , Male , Middle Aged , Myopathies, Nemaline/genetics , Myopathies, Nemaline/pathology , Pedigree
9.
Clin Chem Lab Med ; 48(10): 1409-14, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20578970

ABSTRACT

BACKGROUND: Filamin myopathy is a neuromuscular disorder manifesting with predominantly limb-girdle muscle weakness and in many patients with diaphragm paralysis and cardiomyopathy, caused by mutations in the filamin C (FLNC) gene. Molecular diagnosis of filamin myopathy based on direct DNA sequencing of coding exons is compromised by the presence of a high homology pseudogene (pseFLNC) located approximately 53.6 kb downstream of the functional FLNC gene on chromosome 7q. METHODS: Molecular cloning, RT-PCR and real-time PCR methods were used to detect sequence differences between the FLNC and pseFLNC that are implicated in known or potential molecular diagnostic errors. Overall, 50 patients with a phenotype resembling filamin myopathy have been screened for mutations in FLNC. RESULTS: FLNC sequence inconsistencies caused by the interference from pseFLNC were identified and diagnostic errors involving, in particular, the detection of the most frequent disease-causing FLNC p.W2710X mutation resolved. Mismatches between the FLNC and pseFLNC sequences were tabulated for future use. CONCLUSIONS: We devise a strategy that allows one to discern mutations occurring in the functional FLNC from those harbored in pseFLNC, thus preventing possible complications in future research and patient genetic testing.


Subject(s)
Contractile Proteins/genetics , DNA/genetics , Microfilament Proteins/genetics , Molecular Diagnostic Techniques , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Sequence Analysis, DNA , Base Sequence , Chromosomes, Human, Pair 7/genetics , Cloning, Molecular , Exons , Filamins , Humans , Mutation , Reverse Transcriptase Polymerase Chain Reaction
10.
PLoS One ; 14(8): e0220512, 2019.
Article in English | MEDLINE | ID: mdl-31404076

ABSTRACT

Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative single nucleotide variant (SNV) or indel due to incomplete coverage of the entire coding region of the genome, in addition to accurate detection of larger structural variants (SVs) and copy number variants (CNVs). Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n = 40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare SNV and indel classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within ET families was also performed. Prioritization of candidate genes identified within families was performed using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a role for these genes in ET disease pathogenesis.


Subject(s)
Essential Tremor/genetics , Genetic Variation/genetics , Whole Genome Sequencing , Adult , Family , Female , Genetic Predisposition to Disease/genetics , Genetic Variation/physiology , Humans , Male , Middle Aged , Pedigree
11.
Sci Rep ; 8(1): 7664, 2018 05 16.
Article in English | MEDLINE | ID: mdl-29769701

ABSTRACT

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K+ channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K+ channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.


Subject(s)
Brain/pathology , Drosophila melanogaster/metabolism , Essential Tremor/complications , Models, Neurological , Mutation , Potassium Channels, Voltage-Gated/metabolism , Sleep Wake Disorders/etiology , Adult , Algorithms , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/growth & development , Animals, Genetically Modified/metabolism , Behavior, Animal , Brain/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Essential Tremor/physiopathology , Female , Humans , Ion Channel Gating , Male , Potassium Channels, Voltage-Gated/genetics , Sleep Wake Disorders/pathology , Wings, Animal/physiopathology , Young Adult
12.
Spiritual Clin Pract (Wash D C ) ; 4(1): 43-63, 2017 Mar.
Article in English | MEDLINE | ID: mdl-29057276

ABSTRACT

RATIONALE: Possible genetic correlates of spirituality and depression have been identified in community samples. We investigate some of the previously identified candidates in a sample of families at both high and low-risk for depression. METHOD: Offspring and grandchildren of individuals at high and low-risk for depression, participating in a multi-wave thirty-year longitudinal study, were assessed for seven SNPS drawn from four single gene candidates associated with systems implicated in both depression and spirituality: Serotonin (5-HT1B and 5-HT2A), Dopamine (DRD2), Oxytocin (OT) and Monoamine Vesicular Transporter (VMAT1). RESULTS: Dopamine (DRD2) Serotonin (5-HT1B), their Transporter (VMAT1) and Oxytocin (OXTR) were positively associated with a high level of importance of spirituality or religion (S/R) in the group at low familial risk for depression. DRD2 minor allele was associated with both lifetime major depressive disorder (MDD) and spirituality in the low-risk group for depression. No SNPs were related to S/R in the group at high familial risk for depression. OXTR was associated with lifetime MDD in the full sample. CONCLUSION: Genes for dopamine, serotonin, their vesicular transporter, and oxytocin may be associated with S/R in people at low familial risk for depression. Genes for dopamine may be associated both with S/R and increased risk for depression in people at low-risk for depression, suggesting a common pathway or physiology to mild to moderate depression. MDD is associated with oxytocin across risk groups. In the high-risk group, phenotypic expression of S/R may be suppressed. IMPLICATIONS: The shared association of DRD2 by S/R and depression, generally found to be inversely related, calls for further research on their common physiological pathways, and the phenotypic expression of these pathways based upon use and environment. Prevention for offspring at high familial risk for depression might include support for the development of child spirituality.

13.
Psychiatry Res ; 253: 211-219, 2017 07.
Article in English | MEDLINE | ID: mdl-28391138

ABSTRACT

The role of the serotonin transporter promoter-linked polymorphism (5-HTTLPR) in psychiatric disease remains unclear. Behavioral traits could serve as alternative outcomes that are stable, precede psychopathology, and capture more sub-clinical variation. We test associations between 5-HTTLPR and (1) behavioral traits and (2) clinical diagnoses of anxiety and depression. Second and third generation participants (N=203, 34.2±13.8 years, 54% female) at high- or low- familial risk for depression (where risk was defined by the presence of major depression in the 1st generation) were assessed longitudinally using the Schedule for Affective Disorders and Schizophrenia-lifetime interview, Barratt Impulsiveness Scale-11, Buss-Perry Aggression Questionnaire, and the NEO-Five Factor Inventory. High (but not low)-risk offspring with two risk (short, s) alleles had higher impulsivity (+13%), hostility (+31%) and neuroticism (+23%). SS was associated higher rates of panic (OR=7.05 [2.44, 20.38], p=0.0003) and phobic (OR=2.68[1.04, 6.93], p=0.04), but not other disorders. Impulsivity accounted for 16% of associations between 5-HTTLPR and panic, and 52% of association between 5-HTTLPR and phobias. We show that 5-HTTLPR predicts higher impulsivity, hostility, and neuroticism, and that impulsivity could serve as a useful independent outcome or intermediary phenotype in genetic studies of anxiety.


Subject(s)
Anxiety Disorders/genetics , Anxiety/genetics , Family/psychology , Serotonin Plasma Membrane Transport Proteins/genetics , Adolescent , Adult , Aggression , Alleles , Child , Depression/genetics , Depressive Disorder, Major/genetics , Female , Genotype , Hostility , Humans , Impulsive Behavior , Male , Middle Aged , Phenotype , Polymorphism, Genetic , Promoter Regions, Genetic , Risk Factors , Surveys and Questionnaires , Young Adult
14.
Psychiatry Res ; 245: 387-391, 2016 Nov 30.
Article in English | MEDLINE | ID: mdl-27611068

ABSTRACT

Maternal smoking during pregnancy is associated with a number of adverse offspring outcomes. In the present study, based on 209 offspring from a 3-generation family study of depression, we show that the effects of prenatal exposure on offspring externalizing psychopathology (conduct, substance use disorder) is more pronounced in the presence of lower-expressing brain derived neurotrophic factor (BDNF) gene variants. BDNF plays an important role in the development and survival of neural circuits. Individuals with low-expressing variants who are further exposed to prenatal tobacco smoke may be most vulnerable to a spectrum of behavioral disorders that depend on these circuits.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Prenatal Exposure Delayed Effects , Problem Behavior , Smoking/adverse effects , Substance-Related Disorders/etiology , Adult , Female , Humans , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Risk
15.
Psychiatry Res Neuroimaging ; 248: 83-93, 2016 Feb 28.
Article in English | MEDLINE | ID: mdl-26774425

ABSTRACT

Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The "s" allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.


Subject(s)
Cerebral Cortex/pathology , Depressive Disorder, Major/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin/metabolism , Signal Transduction/genetics , Adolescent , Adult , Child , Female , Genetic Predisposition to Disease , Genotype , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Pedigree , Polymorphism, Genetic , Risk , Young Adult
16.
Psychiatry Res ; 228(1): 170-3, 2015 Jul 30.
Article in English | MEDLINE | ID: mdl-25920807

ABSTRACT

The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N = 192) as compared to low (N = 101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences.


Subject(s)
Depressive Disorder, Major/genetics , Genetic Predisposition to Disease , Serotonin Plasma Membrane Transport Proteins/genetics , Genotype , Humans , Pedigree , Polymorphism, Genetic , Risk , Severity of Illness Index
17.
J Diabetes ; 4(3): 238-42, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22151254

ABSTRACT

BACKGROUND: Recent genome-wide association studies (GWAS) have identified more than 40 common sequence variants associated with type 2 diabetes (T2D). However, the results are not always the same in populations with differing genetic backgrounds. In the present study, we evaluated a hypothesis that a North Asian population living in a geographic area with unusually harsh environmental conditions would develop unique genetic risks. METHODS: A population-based association study was performed with 21 single-nucleotide polymorphisms (SNPs) in nine genes selected according to the results of GWAS conducted in other populations. The study participants included 393 full-heritage Mongolian individuals (177 diagnosed with T2D and 216 matched controls). Genotyping was performed by TaqMan methodology. RESULTS: The strongest association was detected with SNPs located within the potassium channel-coding genes KCNQ1 (highest odds ratio [OR] = 1.92; P = 3.4 × 10(-5) ) and ABCC8 (OR = 1.79; P = 5 × 10(-4) ). Genetic variants identified as strongly influencing the risk of T2D in other populations (e.g. KCNJ11 or TCF7L2) did not show significant association in Mongolia. CONCLUSIONS: The strongest T2D risk-associated SNPs in Mongolians are located within two of three tested potassium channel-coding genes. Accumulated variations in these genes may be related to the exposure to harsh environmental conditions.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease/genetics , KCNQ1 Potassium Channel/genetics , Polymorphism, Single Nucleotide , ATP-Binding Cassette Transporters/genetics , Alleles , Gene Frequency , Gene-Environment Interaction , Genome-Wide Association Study , Genotype , Humans , Introns/genetics , Linkage Disequilibrium , Middle Aged , Mongolia , Potassium Channels, Inwardly Rectifying/genetics , Receptors, Drug/genetics , Risk Factors , Sulfonylurea Receptors
18.
Neuromuscul Disord ; 21(8): 533-42, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21676617

ABSTRACT

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRYAB, MYOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 MFM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in MYOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis.


Subject(s)
Muscular Diseases/classification , Muscular Diseases/pathology , Myofibrils/pathology , Phenotype , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , Age of Onset , Aged , Biopsy , Connectin , Cytoskeletal Proteins/genetics , Desmin/genetics , Female , Humans , LIM Domain Proteins/genetics , Magnetic Resonance Imaging , Male , Microfilament Proteins , Middle Aged , Muscle Proteins/genetics , Muscular Diseases/genetics , Mutation/genetics , Retrospective Studies , Spain , Young Adult
19.
Neuromuscul Disord ; 20(7): 438-42, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20605452

ABSTRACT

Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by disintegration of myofibrils. The inheritance pattern is commonly autosomal dominant, but there has been a striking absence of secondary cases noted in a BAG3-associated subtype. We studied three families with BAG3 p.Pro209Leu mutation showing a severe phenotype of myofibrillar myopathy and axonal neuropathy with giant axons. In one family, transmission to a pair of siblings has occurred from their asymptomatic father who showed somatic mosaicism. In two other families, neither of the parents was affected or showed detectable level of somatic mosaicism. These observations suggest that the BAG3 variant of myofibrillar myopathy may result from a spontaneous mutation at an early point of embryonic development and that transmission from a mosaic parent may occur more than once. The study underlines the importance of parental evaluation as it may have implications for genetic counseling.


Subject(s)
Actin Cytoskeleton/pathology , Adaptor Proteins, Signal Transducing/genetics , Family Health , Muscular Diseases/genetics , Muscular Diseases/pathology , Mutation/genetics , Actin Cytoskeleton/ultrastructure , Adolescent , Adult , Apoptosis Regulatory Proteins , Child , DNA Mutational Analysis , Female , Genotype , Humans , Leucine/genetics , Male , Microscopy, Electron, Scanning , Muscular Diseases/physiopathology , Phenotype , Proline/genetics , Sural Nerve/pathology , Sural Nerve/ultrastructure , Young Adult
20.
Eur J Hum Genet ; 17(5): 656-63, 2009 May.
Article in English | MEDLINE | ID: mdl-19050726

ABSTRACT

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.


Subject(s)
Contractile Proteins/genetics , Microfilament Proteins/genetics , Muscular Diseases/genetics , Repetitive Sequences, Nucleic Acid/genetics , Sequence Deletion , Amino Acid Sequence , Contractile Proteins/metabolism , DNA Mutational Analysis , Family Health , Female , Filamins , Humans , Immunoblotting , Immunoglobulins/genetics , Immunohistochemistry , Male , Microfilament Proteins/metabolism , Microscopy, Electron , Molecular Sequence Data , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Muscular Diseases/metabolism , Muscular Diseases/pathology , Mutation , Myofibrils/metabolism , Myofibrils/pathology , Sequence Homology, Amino Acid
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