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1.  Handedness and the X chromosome: The role of androgen receptor CAG-repeat length 
Scientific Reports  2015;5:8325.
Prenatal androgen exposure has been suggested to be one of the factors influencing handedness, making the androgen receptor gene (AR) a likely candidate gene for individual differences in handedness. Here, we examined the relationship between the length of the CAG-repeat in AR and different handedness phenotypes in a sample of healthy adults of both sexes (n = 1057). Since AR is located on the X chromosome, statistical analyses in women heterozygous for CAG-repeat lengths are complicated by X chromosome inactivation. We thus analyzed a sample of women that were homozygous for the CAG-repeat length (n = 77). Mixed-handedness in men was significantly associated with longer CAG-repeat blocks and women homozygous for longer CAG-repeats showed a tendency for stronger left-handedness. These results suggest that handedness in both sexes is associated with the AR CAG-repeat length, with longer repeats being related to a higher incidence of non-right-handedness. Since longer CAG-repeat blocks have been linked to less efficient AR function, these results implicate that differences in AR signaling in the developing brain might be one of the factors that determine individual differences in brain lateralization.
PMCID: PMC4321186  PMID: 25659367
2.  Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene 
Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.
PMCID: PMC4295438  PMID: 25642194
episodic ataxia type 1; hyperthermia; sleep; migraine; Shaker potassium channels; C185W
3.  Handedness genetics: considering the phenotype 
Frontiers in Psychology  2014;5:1300.
PMCID: PMC4227468  PMID: 25426097
handedness; genotype; phenotype; laterality; hemispheric asymmetry; hemispheric lateralization; motor control; ontogenesis
4.  PCSK6 VNTR Polymorphism Is Associated with Degree of Handedness but Not Direction of Handedness 
PLoS ONE  2013;8(6):e67251.
Although the left and right human cerebral hemispheres differ both functionally and anatomically, the mechanisms that underlie the establishment of these hemispheric specializations, as well as their physiological and behavioral implications, remain largely unknown. Since cerebral asymmetry is strongly correlated with handedness, and handedness is assumed to be influenced by a number of genetic and environmental factors, we performed an association study of LRRTM1 rs6733871 and a number of polymorphisms in PCSK6 and different aspects of handedness assessed with the Edinburgh handedness inventory in a sample of unrelated healthy adults (n = 1113). An intronic 33bp variable-number tandem repeat (VNTR) polymorphism in PCSK6 (rs10523972) shows a significant association (significance threshold: p<0.0025, adjusted for multiple comparisons) with a handedness category comparison (P = 0.0005) and degree of handedness (P = 0.001). These results provide further evidence for the role of PCSK6 as candidate for involvement in the biological mechanisms that underlie the establishment of normal brain lateralization and thus handedness and support the assumption that the degree of handedness, instead the direction, may be the more appropriate indicator of cerebral organization.
PMCID: PMC3695088  PMID: 23826248
5.  Cholecystokinin A Receptor (CCKAR) Gene Variation Is Associated with Language Lateralization 
PLoS ONE  2013;8(1):e53643.
Schizophrenia is a psychiatric disorder associated with atypical handedness and language lateralization. However, the molecular mechanisms underlying these functional changes are still poorly understood. Therefore, the present study was aimed at investigating whether variation in schizophrenia-related genes modulates individual lateralization patterns. To this end, we genotyped 16 single nucleotide polymorphisms that have previously been linked to schizophrenia on a meta-analysis level in a sample of 444 genetically unrelated healthy participants and examined the association of these polymorphisms with handedness, footedness and language lateralization. We found a significant association of the cholecystokinin-A receptor (CCKAR) gene variation rs1800857 and language lateralization assessed using the dichotic listening task. Individuals carrying the schizophrenia risk allele C of this polymorphism showed a marked reduction of the typical left-hemispheric dominance for language processing. Since the cholecystokinin A receptor is involved in dopamine release in the central nervous system, these findings suggest that genetic variation in this receptor may modulate language lateralization due to its impact on dopaminergic pathways.
PMCID: PMC3544920  PMID: 23341962
6.  Hepatic mitochondrial dysfunction in Friedreich Ataxia 
BMC Neurology  2011;11:145.
Mitochondrial dysfunction due to respiratory chain impairment is a key feature in pathogenesis of Friedreich ataxia. Friedreich ataxia affects the nervous system, heart and pancreas.
We assessed hepatic mitochondrial function by 13C-methionine-breath-test in 16 Friedreich ataxia patients and matched healthy controls.
Patients exhaled significantly smaller amounts of 13CO2 over 90 minutes. Maximal exhaled percentage dose of 13CO2 recovery was reduced compared to controls.
13C-methionine-breath-test indicates subclinical hepatic mitochondrial dysfunction in Friedreich ataxia but did not correlate with GAA repeat lengths, disease duration or disease severity.
PMCID: PMC3226643  PMID: 22085827
13C-methionine; breath test; Friedreich; Ataxia; neurodegeneration
7.  NMDA receptor gene variations as modifiers in Huntington disease: a replication study 
PLoS Currents  2011;3:RRN1247.
Several candidate modifier genes which, in addition to the pathogenic CAG repeat expansion, influence the age at onset (AO) in Huntington disease (HD) have already been described. The aim of this study was to replicate association of variations in the N-methyl D-aspartate receptor subtype genes GRIN2A and GRIN2B in the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). The analyses did replicate the association reported between the GRIN2A rs2650427 variation and AO in the entire cohort. Yet, when subjects were stratified by AO subtypes, we found nominally significant evidence for an association of the GRIN2A rs1969060 variation and the GRIN2B rs1806201 variation. These findings further implicate the N-methyl D-aspartate receptor subtype genes as loci containing variation associated with AO in HD.
PMCID: PMC3186947  PMID: 21989477
8.  PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease 
Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.
In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.
These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.
PMCID: PMC3117738  PMID: 21595933
9.  Efficacy of Fumaric Acid Esters in the R6/2 and YAC128 Models of Huntington's Disease 
PLoS ONE  2011;6(1):e16172.
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor “nuclear factor E2-related factor 2” (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80–90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted.
PMCID: PMC3031519  PMID: 21297955
10.  PGC-1alpha as modifier of onset age in Huntington disease 
Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD.
PMCID: PMC2644307  PMID: 19200361
11.  Genomic NGFB variation and multiple sclerosis in a case control study 
BMC Medical Genetics  2008;9:107.
Nerve growth factor β (NGFB) is involved in cell proliferation and survival, and it is a mediator of the immune response. ProNGF, the precursor protein of NGFB, has been shown to induce cell death via interaction with the p75 neurotrophin receptor. In addition, this neurotrophin is differentially expressed in males and females. Hence NGFB is a good candidate to influence the course of multiple sclerosis (MS), much like in the murine model of experimental autoimmune encephalomyelitis (EAE).
Ten single nucleotide polymorphisms (SNPs) were genotyped in the NGFB gene in up to 1120 unrelated MS patients and 869 controls. Expression analyses were performed for selected MS patients in order to elucidate the possible functional relevance of the SNPs.
Significant association of NGFB variations with MS is evident for two SNPs. NGFB mRNA seems to be expressed in sex- and disease progression-related manner in peripheral blood mononuclear cells.
NGFB variation and expression levels appear as modulating factors in the development of MS.
PMCID: PMC2613874  PMID: 19063739
12.  Autosomal dominant hereditary spastic paraplegia: Novel mutations in the REEP1 gene (SPG31) 
BMC Medical Genetics  2008;9:71.
Mutations in the SPG4 gene (spastin) and in the SPG3A gene (atlastin) account for the majority of 'pure' autosomal dominant form of hereditary spastic paraplegia (HSP). Recently, mutations in the REEP1 gene were identified to cause autosomal dominant HSP type SPG31. The purpose of this study was to determine the prevalence of REEP1 mutations in a cohort of 162 unrelated Caucasian index patients with 'pure' HSP and a positive family history (at least two persons per family presented symptoms).
162 patients were screened for mutations by, both, DHPLC and direct sequencing.
Ten mutations were identified in the REEP1 gene, these included eight novel mutations comprising small insertions/deletions causing frame shifts and subsequently premature stop codons, one nonsense mutation and one splice site mutation as well as two missense mutations. Both missense mutations and the splice site mutation were not identified in 170 control subjects.
In our HSP cohort we found pathogenic mutations in 4.3% of cases with autosomal dominant inheritance. Our results confirm the previously observed mutation range of 3% to 6.5%, respectively, and they widen the spectrum of REEP1 mutations.
PMCID: PMC2492855  PMID: 18644145
13.  No association between polymorphisms in the BDNF gene and age at onset in Huntington disease 
BMC Medical Genetics  2006;7:79.
Recent evidence suggests that brain-derived neurotrophic factor (BDNF) is an attractive candidate for modifying age at onset (AO) in Huntington disease (HD). In particular, the functional Val66Met polymorphism appeared to exert a significant effect. Here we evaluate BDNF variability with respect to AO of HD using markers that represent the entire locus.
Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients.
Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO.
We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO.
PMCID: PMC1637098  PMID: 17096834
14.  Failure to confirm influence of Methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease 
Huntington disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Recently, suggestive association has been reported between a single nucleotide polymorphism (SNP; rs1801131, also known as A1298C) in the methyltetrahydrofolate reductase (MTHFR) gene and AO of HD. 5,10-MTHFR is a key enzyme in the folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using part of a previously established study cohort plus additional patients and appropriate statistical methods, we reinvestigated two polymorphisms in the MTHFR gene, C677T and A1298C, as well as their association with AO in 167 HD patients.
There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof.
Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients.
PMCID: PMC1327683  PMID: 16372906
15.  On the genetic involvement of apoptosis-related genes in Crohn's disease as revealed by an extended association screen using 245 markers: no evidence for new predisposing factors 
Crohn's disease (CD) presents as an inflammatory barrier disease with characteristic destructive processes in the intestinal wall. Although the pathomechanisms of CD are still not exactly understood, there is evidence that, in addition to e.g. bacterial colonisation, genetic predisposition contributes to the development of CD. In order to search for predisposing genetic factors we scrutinised 245 microsatellite markers in a population-based linkage mapping study. These microsatellites cover gene loci the encoded protein of which take part in the regulation of apoptosis and (innate) immune processes. Respective loci contribute to the activation/suppression of apoptosis, are involved in signal transduction and cell cycle regulators or they belong to the tumor necrosis factor superfamily, caspase related genes or the BCL2 family. Furthermore, several cytokines as well as chemokines were included. The approach is based on three steps: analyzing pooled DNAs of patients and controls, verification of significantly differing microsatellite markers by genotyping individual DNA samples and, finally, additional reinvestigation of the respective gene in the region covered by the associated microsatellite by analysing single-nucleotide polymorphisms (SNPs). Using this step-wise process we were unable to demonstrate evidence for genetic predisposition of the chosen apoptosis- and immunity-related genes with respect to susceptibility for CD.
PMCID: PMC1315346  PMID: 16318629
16.  Age at onset of Huntington disease is not modulated by the R72P variation in TP53 and the R196K variation in the gene coding for the human caspase activated DNase (hCAD) 
BMC Medical Genetics  2005;6:35.
TP53 is an attractive candidate for modifying age of onset (AO) in Huntington disease (HD): The amino-terminus of the mutated huntingtin (htt) exon 1 translation product has functional properties which may affect critically the TP53 pathway in HD neurons. The pathogenic domain of mutant htt interacts with nuclear transcription factors, and it potentially modulates TP53-induced transcriptional events. A single nucleotide polymorphism (SNP) resulting in the R72P exchange in TP53 protein might modulate the variation in AO. In addition, also the R196K replacement in human caspase activated DNase (hCAD) may theoretically affect the AO.
We have genotyped the polymorphisms R72P and R196K in a well established cohort of 167 unrelated HD patients.
The expanded CAG repeat explained 30.8% of the variance in AO. Adding the genotypes of the SNPs investigated did not affect the variance of the AO variance explained.
In this replication study, no association was found explaining a significant amount of the variability in AO of HD thus contradicting a recent report.
PMCID: PMC1253512  PMID: 16202123
17.  Glutathione S-Transferase Ω 1 variation does not influence age at onset of Huntington's disease 
Huntington's disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Circumstantial evidence suggests that additional features of the HD course are based on genetic traits. Therefore, it may be possible to investigate the genetic background of HD, i.e. to map the loci underlying the development and progression of the disease. Recently an association of Glutathione S-Transferase Ω 1 (GSTO1) and possibly of GSTO2 with AO was demonstrated for, both, Alzheimer's (AD) and Parkinson's disease (PD).
We have genotyped the polymorphisms rs4925 GSTO1 and rs2297235 GSTO2 in 232 patients with HD and 228 controls.
After genotyping GSTO1 and GSTO2 polymorphisms, firstly there was no statistically significant difference in AO for HD patients, as well as secondly for HD patients vs. controls concerning, both, genotype and allele frequencies, respectively.
The GSTO1 and GSTO2 genes flanked by the investigated polymorphisms are not comprised in a primary candidate region influencing AO in HD.
PMCID: PMC394327  PMID: 15040808

Results 1-17 (17)