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Laboratories
Genetic Neurobiology
The Laboratory of Genetic Neurobiology currently focuses on five interrelated
projects:
- A search for the genetic causes of neurodegenerative diseases, particularly
those that affect the basal ganglia or the cerebellum. In the last two
years we have found the cause of two of these disorders, as described
below. We are searching for additional mutations in our collection of
DNA from several hundred individuals with unidentified disorders of the
basal ganglia and cerebellum.
- A search for the genetic etiology of psychiatric disorders, such as
bipolar affective disorder and schizophrenia, using a candidate gene
approach. Our current work is designed to test the hypotheses that repeat
expansions may contribute to the genetic vulnerability of these disorders
(Margolis et al, 1999).
- A search for genetic factors that influence the diagnosis, onset age
or progression of Huntington's disease. This work is carried out in conjunction
with the Baltimore
HD Center, and has led to changes in the recommended diagnostic test
for HD (Margolis et al, 1999).
- Investigation of the pathogenesis of a disorder first described by
our group, spinocerebellar ataxia type 12 (Holmes et al, 1999; O'Hearn
et al, 2001). We have determined that the disorder appears to be caused
by an expansion mutation of a CAG repeat in the 5' region of the gene
PPP2R2B, which encodes a regulatory subunit of the phosphatase PP2A.
Current work is designed to determine the effect of this expansion on
expression of PPP2R2B, and to develop cell and animal models of the disease.
- Investigation of the pathogenesis of Huntington's disease like-2 (HDL2),
another disorder clinically (Margolis et al, 2001) and genetically (Holmes,
2001) characterized in our laboratory. HDL2 is clinically indistinguishable
from HD but is caused by a CTG expansion in an alternatively spliced
exon of the gene junctophilin-3. Current research is focused on developing
cell and animal models of HDL2 pathogenesis, and further defining the
clinical, genetic, and epidemiological characteristics of the disease
in humans.
Laboratory Faculty
Russell L. Margolis, M.D., Director
Susan E. Holmes, Ph.D.
Laboratory Staff
Fellows:
Doda Rudnicki, Ph.D.
Nancy Sachs, Ph.D.
Technicians:
Colleen Callahan, B.A.
John Hwang, B.A.
Abdulgafoor M. Bachani, B.A.
Amira Pavlovich, B.A.
Recent Publications
Holmes SE, O'Hearn E, Callahan C, Hwang HS, Rosenblatt A, Ingersoll-Ashworth
RG, Fleisher A, Stevanin G, Brice A, Potter NT, Ross CA, Margolis RL. A CTG
trinucleotide repeat expansion in Junctophilin 3 is associated with
Huntington's Disease-Like 2 (HDL2). Nature Genetics, 29 (2001): 377-378,
2001
Margolis RL, McInnis MG, Rosenblatt A, Ross CA. Trinucleotide repeat expansion
and neuropsychiatric disease. Archives of General Psychiatry, 56
(1999):1019-1031.
Holmes SE, O'Hearn E, McInnis MG, Kwak NG, Gorelick-Feldman DA,
Kleiderlein JK, Callahan C, Sherr M, Sharp AH, Sumner AJ, Ashworth
RG, Ananth U, Seltzer W, Vieria-Saecker AM, Epplen JT, Reiss O,
Ross CA, Margolis RL. Expansion of a novel CAG trinucleotide repeat
in the 5' region of PPP2R2B is associated with SCA12, Nature
Genetics, 23 (1999): 391-392.
Acknowledgements
Work on all of these projects is performed in close collaboration with Dr.
Christopher Ross, Dr. Adam Rosenblatt, and Dr. Akira Sawa within the Division
of Neurobiology, Drs. Troncoso and Borchelt in the Department of Neuropathology,
and Drs. McInnis, Potash, and DePaulo of the Division of Psychiatric Genetics,
and Dr. Elizabeth O'Hearn in the Department of Neurology. |
