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M Burmeister

Publications and source records attributed to M Burmeister.

At least 19 recordsLinked to original sources
PubMed2006

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders.

Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders.

Antidepressive Agents↗
PubMed2004

Genetic analysis of the neuronal and ubiquitous AP-3 adaptor complexes reveals divergent functions in brain.

Neurons express adaptor (AP)-3 complexes assembled with either ubiquitous (beta3A) or neuronal-specific (beta3B) beta3 isoforms. However, it is unknown whether these complexes indeed perform distinct functions in neuronal tissue. Here, we explore this hypothesis by using genetically engineered mouse models lacking either beta3A- or beta3B-containing AP-3 complexes. Somatic and neurological phenotypes were specifically associated with the ubiquitous and neuronal adaptor deficiencies, respectively. At the cellular level, AP-3 isoforms were localized to distinct neuronal domains. beta3B-containing AP-3 complexes were preferentially targeted to neuronal processes. Consistently, beta3B deficiency compromised synaptic zinc stores assessed by Timm's staining and the synaptic vesicle targeting of membrane proteins involved in zinc uptake (ZnT3 and ClC-3). Surprisingly, despite the lack of neurological symptoms, beta3A-deficient mouse brain possessed significantly increased synaptic zinc stores and synaptic vesicle content of ZnT3 and ClC-3. These observations indicate that the functions of beta3A- and beta3B-containing complexes are distinct and divergent. Our results suggest that concerted nonredundant functions of neuronal and ubiquitous AP-3 provide a mechanism to control the levels of selected membrane proteins in synaptic vesicles.

Adaptor Protein Complex 3↗
PubMed2001

Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.

Alleles↗
PubMed2001

Severe vestibular and auditory impairment in three alleles of Ames waltzer (av) mice.

The genetic and physiological characterization of circling, hearing-impaired mouse mutants has greatly facilitated our understanding of non-syndromic sensorineural deafness, the most common form of hereditary human hearing loss. Here we report the first phenotypic characterization of three alleles of Ames waltzer (av). Neither electrical potentials (auditory brainstem response) nor behavioral responses to sound could be evoked in any of the three alleles at any age or frequency. However, the endocochlear potential was found to be normal, indicating that the primary pathology is not in the stria vascularis. To determine the earliest changes and help identify the primary causes of deafness in av, we performed morphological studies in 15-16 day old mutants, just prior to the maturation of the cochlea. Although av(2J) is slightly more affected than the other two alleles, our studies show a high similarity between all three alleles. The first detectable changes are observed in the stereocilia and cytoplasm of hair cells, and in the cellular shape and microvilli of supporting cells. These changes are followed by degeneration of the cochlear and vestibular neuroepithelium.

Alleles↗
PubMed2001

Subarachnoid sufentanil for early postoperative pain management in orthopedic patients: a placebo-controlled, double-blind study using spinal microcatheters.

BACKGROUND: Continuous spinal anesthesia is frequently used for intraoperative anesthesia but rarely for postoperative pain management. Because even small doses of local anesthetics can be associated with motor deficits, subarachnoid opioid injection may be an alternative. METHODS: Eighty patients randomly received a subarachnoid injection of 10 microg sufentanil, 5 mg bupivacaine, 2.5 microg sufentanil plus 2.5 mg bupivacaine, or saline through 28-gauge spinal microcatheters for early postoperative pain relief after major lower-limb surgery (n = 20 in each group). Hemodynamic and respiratory parameters, pain scores, and motor function were monitored, and sufentanil concentrations in plasma and cerebrospinal fluid were measured. Ten additional patients received up to three repetitive injections of 10 microg sufentanil over 24 h. RESULTS: All drugs provided excellent pain relief within 15 min after injection, lasting 128 +/- 61 min with sufentanil, 146 +/- 74 min with bupivacaine, and 167 +/- 78 min with the mixture. Patients receiving bupivacaine showed the highest cephalad extension of sensory block (median, T6) and the most intense motor block, whereas patients given only sufentanil had no motor deficit. The duration of analgesia was shorter after subsequent sufentanil injection (100-115 min) than after the first injection (198 +/- 70 min). Six of 50 patients with sufentanil experienced a short episode of respiratory depression within 30 min after the first injection. Cerebrospinal fluid concentrations of sufentanil peaked at 5 min after injection (183 +/- 167 ng/ml) but were at the level of detection in the plasma. CONCLUSIONS: Sufentanil injected through microspinal catheters provided profound pain relief without impairing motor function when compared with bupivacaine. However, close monitoring remains mandatory in this setting.

Adult↗
PubMed2000

DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24.

Using linkage analysis, we identified a novel dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational United States family of Czech descent. On the basis of recombinations in affected individuals, we determined that DFNA25 is located in a 20-cM region of chromosome 12q21-24 between D12S327 (centromeric) and D12S84 (telomeric), with a maximum two-point LOD score of 6.82, at recombination fraction.041, for D12S1030. Candidate genes in this region include ATP2A2, ATP2B1, UBE3B, and VR-OAC. DFNA25 may be the human ortholog of bronx waltzer (bv).

Adult↗
PubMed2000

Recent progress in psychiatric genetics-some hope but no hype.

The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.

Epistasis, Genetic↗
PubMed2000

Partial rescue of the ocular retardation phenotype by genetic modifiers.

The or(J) allele of the murine ocular retardation mutation is caused by a premature stop codon in the homeodomain of the Chx10 gene. When expressed on an inbred 129/Sv strain, the or(J) phenotype is characterized by microphthalmia and a thin, poorly differentiated retina in which the peripheral portion is affected to a greater extent than the central portion. Such mutant retinae lack differentiated bipolar cells and the optic nerve typically fails to form, leading to blindness. Here, we show that progeny from an outcrossed backcross between 129/Sv-or(J) /or(J) and Mus musculus castaneus produce animals that are homozygous for the or(J) mutation and exhibit a much ameliorated eye phenotype. Although not of normal size, such modified or(J) eyes are significantly larger than those in 129/Sv-or(J) /or(J) mice, and contain a better organized retina which includes bipolar cells. Furthermore, optic nerves are frequently present, and the eyes show a degree of function as reflected by electroretinogram and pupillary response. As in 129/Sv-or(J) /or(J) mice, however, modified or(J) eyes show incomplete growth and a lack of cell differentiation in the periphery of the retina. The selective, and apparently nonmodifiable, effect of the ocular retardation phenotype on the periphery of the retina indicates that Chx10 plays an important role in the central-to-peripheral gradient of retinal development. These findings demonstrate that the ocular retardation phenotype can be greatly modified by the genetic background, and help to define a role for Chx10 in ocular development.

Animals↗
PubMed2000

Identification of a novel LIM domain gene, LMCD1, and chromosomal localization in human and mouse.

A new human LIM domain gene LMCD1 was identified from RT-PCR products, and partial sequencing of two expressed sequence tag clones flanking the assembled cDNA contig revealed a 1743-bp full-length cDNA with 1098-bp open reading frame. The coding sequence of the putative protein is 57.6% identical to murine testin 1 gene (Tes1), whereas the predicted 365-amino-acid protein is 49.5% identical to the mouse Tes1 protein. The predicted LMCD1 protein contains a novel cysteine-rich domain residing in the amino-terminal region and two LIM domains with regular spacing in the carboxy-terminal region. Northern blot analysis indicated expression of the 1.7-kb transcript in many tissues, with highest abundance in skeletal muscle. Radiation hybrid mapping localized human LMCD1 to the telomeric region of chromosome 3p, and genetic mapping assigned the mouse Lmcd1 locus to the central region of chromosome 6.

Amino Acid Sequence↗
PubMed2000

Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints.

A cosmid/bacterial artificial chromosome (BAC) contiguous (contig) map of human chromosome (HSA) 19p13.3 has been constructed, and over 50 genes have been localized to the contig. Genes and anonymous ESTs from approximately 4000 kb of human 19p13.3 were placed on the central mouse chromosome 10 map by genetic mapping and pulsed-field gel electrophoresis (PFGE) analysis. A region of approximately 2500 kb of HSA 19p13.3 is collinear to mouse chromosome (MMU) 10. In contrast, the adjacent approximately 1200 kb are inverted. Two genes are located in a 50-kb region after the inversion on MMU 10, followed by a region of homology to mouse chromosome 17. The synteny breakpoint and one of the inversion breakpoints has been localized to sequenced regions in human <5 kb in size. Both breakpoints are rich in simple tandem repeats, including (TCTG)n, (CT)n, and (GTCTCT)n, suggesting that simple repeat sequences may be involved in chromosome breaks during evolution. The overall size of the region in mouse is smaller, although no large regions are missing. Comparing the physical maps to the genetic maps showed that in contrast to the higher-than-average rate of genetic recombination in gene-rich telomeric region on HSA 19p13.3, the average rate of recombination is lower than expected in the homologous mouse region. This might indicate that a hot spot of recombination may have been lost in mouse or gained in human during evolution, or that the position of sequences along the chromosome (telomeric compared to the middle of a chromosome) is important for recombination rates.

Animals↗
PubMed2000

Effects of vagus nerve stimulation on progressive myoclonus epilepsy of Unverricht-Lundborg type.

PURPOSE: A 34-year-old woman with progressive myoclonus epilepsy of Unverricht-Lundborg type was considered for vagus nerve stimulation (VNS) therapy. METHODS: After demonstration of intractability to multiple antiepileptic regimens and progressive deterioration in cerebellar function, the patient was implanted with a vagus nerve stimulator and followed for 1 year. Neurological status, seizure frequency, and parameter changes were analyzed. RESULTS: VNS therapy resulted in reduction of seizures (more than 90%) and a significant improvement in cerebellar function demonstrated on neurological examination. The patient reported improved quality of life based in part on her ability to perform activities of daily living. CONCLUSIONS: VNS therapy may be considered a treatment option for progressive myoclonus epilepsy. The effects of VNS on seizure control and cerebellar dysfunction may provide clues to the underlying mechanism(s) of action.

Adult↗
PubMed1999

Hippocampal auditory gating in the hyperactive mocha mouse.

The mouse mutants mocha (mh) and mocha2J (mh2J) result from separate mutations in the same gene (AP-3 delta) that arose independently on different backgrounds of inbred strains. They exhibit a neurological phenotype that includes hyperactivity, an epileptiform EEG and changes in the basic function of the hippocampus. Depth electrode recordings of hippocampal auditory evoked potentials revealed that the response to the first of two paired tones was significantly enhanced in mocha and mocha2J, as compared with littermate controls. The pronounced theta rhythm characteristic of unanesthetized mocha mice was not observed in these chloral-hydrate anesthetized mice, whereas spike discharge activity was frequently present in the recordings.

Acoustic Stimulation↗
PubMed1999

Basic concepts in the study of diseases with complex genetics.

Most diseases run in families--this is also true of virtually all psychiatric disorders. Twin and adoption studies have shown that most psychiatric disorders have a genetic component, yet very few genetic factors are known, as is true for most disorders with a complex genetic origin. Here I review, for nongeneticists, some of the basic terminology and concepts used when studying complex genetic diseases, with examples from psychiatric genetics. This review is intended to help in the understanding and critical evaluation of reports on genetics of psychiatric illnesses in the literature.

Alleles↗
PubMed1999

Deletion of chromosome 2q37 and autism: a distinct subtype?

Several reports have described the occurrence of chromosome abnormalities in autism, a neuro-developmental disorder characterized by social deficits, communication impairment, and a restricted range of interests. These include the fragile X abnormality and 15q duplications. In this report, we describe two cases of chromosome 2q37 and review the literature on this topic. We propose that deletion of the distal portion of the long arm of chromosome 2 (2q37) may be associated with some cases of autism and with a distinct phenotype. Increased awareness of the dysmorphic features associated with 2q37 deletions may aid in the molecular genetic analysis of this chromosome anomaly and clarify its relationship with autism.

Autistic Disorder↗
PubMed1999

Potential associations among genetic markers in the serotonergic system and the antisocial alcoholism subtype.

Alcoholism is transmitted in families. The complexity and heterogeneity of this disorder has made it difficult to identify specific genetic correlates. One design with the potential to do so is the family-based association study, in which the frequencies of genetic polymorphisms are compared between affected and nonaffected members. Reduced central serotonin neurotransmission is associated with features of an antisocial subtype of alcoholism, although a primary deficit has not been traced to a particular component. Genetic markers related to the sertonergic system have been identified, located, and cloned. If associations can be discovered, the development process for pharmacotherapy could be facilitated. In this review, the evidence for the involvement of the serotonergic system in antisocial alcoholism is examined, and the potential for family-based association studies to identify specific components that may be involved is discussed.

Alcoholism↗