burmeister MHRI or Mental Health Research Institute



Senior Associate Research Scientist, Mental Health Research Institute
Associate Professor of Human Genetics
Associate Professor of Human Genetics in Psychiatry

Collection of on-line Papers and Reviews by Burmeister and Colleagues


Research Synopsis: Identification of Genes That Cause Neurological and Psychiatric Disorders

This laboratory's research is aimed at finding genes involved in neurological and psychiatric diseases and behavior. While primarily interested in human disorders, we are using mice as a model system when appropriate. The approach employed, "positional cloning", has recently been used successfully to clone many genes and relies on the precise localization of a gene on the chromosome by genetic means. It does not require any knowledge about the gene's function. For many neurological and psychiatric diseases this is a promising strategy because the biology and physiology of these diseases are not well understood. For the future we anticipate using more large scale technologies such as DNA chips to simultaneously search for many variants that may be implicated in behavior genetics.

Gene for Baltic Myoclonus Epilepsy

Baltic progressive myoclonus epilepsy is a rare disorder, also called Unverricht-Lundborg disease. The mutant gene has been identified to be cystatin B. Why mutations in this gene cause the disease is unknown. In our collection of over two dozen patients we have identified several mutations, the most common of which is a piece of DNA that expands and inactivates the gene. We are collaborating with physicians world-wide to determine if there is a correlation between the size of this expansion and the severity of the disease. We are also evaluating if "atypical" patients have a distinct mutation.

Isolation of a Human Hearing Loss Gene

In collaboration with Irina Bespalova and Marci Lesperance we are in the process of isolating a gene involved in low-frequency hearing loss in a single large family. The gene is located in a well-characterized region of 4p16.3. Currently linkage analysis on newly identified pedigree members is performed to narrow down the genetically defined interval from about 2000 kb to a smaller region. Candidate genes in that interval will be tested for mutations.

Mouse Models for Neurological Disorders

We are studying a mouse mutation, jittery, which is characterized by ataxia and seizures and an allelic mutant (i.e., caused by a mutation in the same gene) called hesitant, characterized by dystonia and ataxia. We have used genetic backcrosses to precisely map the jittery gene as well as two other genes, grizzled and mocha, that genetically map to the same region on the chromosome. Molecular genetic markers and the polymerase chain reaction (PCR) have been used to narrow down the region of these genes to a small interval that was found to be homologous to human Chromosome 19p13.3. This region has been nearly fully sequenced in human, while we have generated a map in mouse and cloned parts of it. All genes that map to this region are being tested for whether or not they are different in the mutant mice. The human genetic disorder Cayman Ataxia maps to the homologous region, and jittery mice may be a model for this rare disease. Physical map of human 19p13.3 & Chromosome 10
A physical map of human 19p13.3, based on data from the Lawrence Livermore National Laboratory, and of mouse Chromosome 10 from our work is shown. Regions in green and yellow on mouse Chromosome 10 are not homologous to 19p13.3. Numbers indicate genetic markers (226 for D10MIT226, etc.). The light blue region symbolizes an inversion between mouse and humans found during our studies. This comparison indicates that the mouse ataxic mutation jittery may be a model for human Cayman ataxia. Several other neurological mutants map in the same region of mouse Chromosome 10. We are cloning the genes involved in these mutations.

Using candidate genes, i.e., genes that genetically map to the region, we have recently identified the gene defect in the mouse mutation mocha. We found that the defect lies in a protein involved in membrane vesicle trafficking explaining many of the deficits of this mouse mutant, for example, why several kinds of membranous vesicles lack storage ability. Similar gene defects are in the human genetic disorder Hermansky-Pudlak syndrome. Most interestingly, the mocha mice are hyperactive, prone to seizures, and have a defect in the innervation of the hippocampus. We have also found that, against expectation, auditory gating is better than normal in these hyperactive mice. A second, milder allele, <mh2J>, caused by insertion of an IAP element, is currently being characterized. We are in the process of constructing a "knock-out" mouse in which we expect to observe only the neurological phenotype and perform behavioral characterization of this mouse to determine if it is a model for human ADHD or other neurological or behavioral disorders.

A fourth mutation, ames waltzer, for deafness and circling behavior, also on mouse Chromosome 10, has been genetically mapped. We have cloned the region around that gene and are determining if any genes are different in this mutant. In collaboration with Richard Altschuler, David Dolan and Yehoash Raphael (U-M Kresge Hearing Research Institute) we are characterizing the defect in this mutant.

In collaboration with Daniel Goldman (MHRI), Mark Hankin (Medical College of Toledo) and Roderick McInnes (Hospital for Sick Children, Toronto) we have used the same strategy to determine the genetic defect of the mouse mutation, ocular retardation, which affects early neural- retina development and causes extremely small eyes (microphthalmia). We have identified the ocular retardation mutation in the gene for <Chx10>, a likely transcription factor. Mutations in this gene may also lead to microphthalmia in humans. In addition, we have found that other genes ("modifier genes") interact with this mutation, and gene mapping strategies have been employed to identify three distinct regions of the genome where such modifier genes are located. Mapping these genes will not only help to elucidate the complex phenotype of the ocular retardation mutation but will also be used as a model for the genetic analysis of complex gene-gene interactions that are likely to play a role in behavioral and psychiatric disorders. A second allele, <or2J>, which in addition is sterile, was shown to be a large (>75 kb) deletion which is postulated to lead to the deletion of a second gene responsible for the sterility.

Genetic Linkage and Association Analysis of Serotonin in Antisocial Alcoholism and a Mouse Model of Aggression

Changes in serotonin, a neurotransmitter, have been shown in patients and mice with aggressive behavior. In collaboration with Elizabeth Hill (U of M Alcoholism Research Center, now University of Detroit - Mercy College) we are recruiting patients with type II alcoholism and their parents. DNA is being extracted and DNA markers for genes involved in serotonin metabolism are being tested. Using a statistical method (HRR and TDT), these data will allow us to conclude which, if any, of the serotonin metabolism genes may contribute to susceptibility to type II alcoholism.

We are in the process of cloning the gene involved in a novel mouse mutant, caused by insertion of a transgene, which was discovered to be exceptionally aggressive. Standardized tests have shown that males are significantly more aggressive and that the aggressiveness co-segregates with the transgene. Cloning of the sites where the transgene is inserted is in progress and is expected to allow us to identify a novel gene involved in aggressive behavior.

Genetics of Depression, Temperament and Behavior

We are collaborating with a number of investigators who are collecting a large number of patients or families who are tested with temperament and behavioral questionaires. For example, the alcoholism families mentioned above also complete a 100 question form that evaluates temperamental scales (e.g. novelty seeking or harm avoidance). In collaboration with Randy Nesse and Alan Weder a large hypertension study has added a temperament scale to their assessment, and a large collaborative study with many investigators at U of M, Stanford and Cornell University New York is obtaining DNA samples from depressed patients treated with Prozak and undergoing a variety of behavioral, hormonal and imaging tests. We are evaluating specific genes in the serotonin and dopamine pathway for involvement in behavioral parameters. However, we are also preparing for the future when large scale testing of thousands of polymorphic variants in DNA samples will become possible. These studies may lead to results how certain genes, in interaction with the environment, might predispose to certain behavioral tendencies, cause the sensitivity of a person to treatment, e.g. Prozak response, or correlate with specific hormonal stress responses.

Representative Publications

Burmeister M: Basic concepts in the study of diseases with complex genetics. Biol Psychiatry 45:522-32, 1999

Kantheti P, Qiao X, Diaz M, Peden AA, Meyer GE, Carskadon SL, Kapfhamer D, Sufalko D, Robinson MS, Noebels NL, Burmeister M: Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21:111-122, 1998.

Zobeley E, Sufalko DS, Adkins S, Burmeister M: Fine genetic and comparative mapping of the deafness mutation Ames waltzer on mouse Chromosome 10. Genomics 50:260-266, 1998.

Bespalova IN, Adkins S, Burmeister M: 3' RACE: Skewed Ratio of Specific to General PCR Primers Improves Yield and Specificity. Biotechniques 24: 575-577, 1998.

Bespalova IN, Adkins SA, Pranzatelli M, Burmeister M: Novel Cystatin B mutation and Novel cystatin B mutation and diagnostic PCR assay in an Unverricht-Lundborg Progressive Myoclonus epilepsy patient. Amer J Med Genet (Neuropsych Genet) 74(5):467-471, 1997.

Burmeister, M., Novak, J., Liang, M.-Y., Basu, S., Ploder, L., Hawes, N.L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V.I., Roderick, T.H., Taylor, B.A., Hankin, M.H. and McInnes, R.R.: Ocular retardation mouse caused by <Chx10> homeobox null allele: Impaired retinal progenitor proliferation and bipolar cell differention. Nature Genet 42(4):376-384 (1996). This article is also discussed in "News and Views" in the same issue.

Kapfhamer, D., Sweet, H.O., Sufalko, D., Warren, S., Johnson, K.R. and Burmeister, M.: The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse Chromosome 10 homologous to 19p13.3. Genomics 35:533-538 (1996).

updated 12/26/2001: This mirror copy maintained at www.nervenet.org by M. Burmeister.