CMMG News

Message From the Director

Six months have passed since the publication of the charter edition of the CMMG News, and during this intervening period significant progress has been made in the CMMG research, educational, and service programs. The CMMG has more than doubled its external grant support, with new grants being awarded to six CMMG primary faculty members as summarized on page 4. In addition to the Research Excellence Fund from the State of Michigan ($2,155,252.00), the CMMG faculty currently have external grant awards with total costs for the current year of $2,909,622.00 and total costs for all years of project support of $8,805,697.00. A major award was received by Minoru S. H. Ko, M.D., Ph.D., from the Exploratory Research for Advanced Technology (ERATO), Research Development Corporation of Japan (JRDC). A faculty profile of Dr. Ko and a description of his research program are presented on page 3.

Orlando J. Miller, M.D., and Dorothy A. Miller, Ph.D., have retired from the faculty and O. J. Miller has been appointed as Professor Emeritus. The CMMG is sponsoring a two-day Symposium on Genetics in Development, Evolution, and Disease in honor of their enormous contributions to the University (story on page 2). Also, eleven new associate or adjunct faculty members have been appointed during the past six months who hold primary appointments in clinical departments in the School of Medicine and its affiliated hospitals. There are currently 18 primary, 10 joint, and 18 associate/adjunct faculty members in the CMMG.

Several new CMMG educational initiatives are in the process of being implemented. The M.S. Degree Program in Genetic Counseling has been approved by the Board of Governors and is currently accepting applicants for the Fall of 1997 class. The CMMG is becoming increasingly involved in the coordination of clinical genetic services at the Detroit Medical Center as part of its emphasis on the development of research, training, and service programs in medical genetics at WSU/DMC. The CMMG News will periodically feature articles on clinical findings, genetics, and research interests at WSU on specific diseases, such as Charcot-Marie-Tooth Disease in this issue (page 8). The CMMG will offer a new course on Methods and Concepts in Molecular Medicine and Genetics beginning in January, 1997. This course will emphasize recombinant DNA technology and molecular genetics and their applications to modern medicine (page 7). The CMMG also offers hands-on training in molecular biology techniques on an individual basis.

The CMMG Macromolecular Core Facility continues to expand its service capabilities. The recent award of an NIH Shared Instrument Grant to eight CMMG faculty members will allow the purchase of a new DNA sequencer that will increase the sequencing capacity of the facility four-fold. The CMMG has also added a new oligonucleotide synthesizer to the facility (page 8). The availability of these new instruments makes it possible to provide more extensive and more rapid service to the WSU/DMC biomedical research community.

"I would like to emphasize that the achievement of the CMMG goals and programs will be greatly facilitated by the involvement of faculty and students throughout the University and its affiliated hospitals."

Many of my comments in this message are expanded upon throughout this second issue of the CMMG News. Once again I would like to emphasize that the achievement of the CMMG goals and programs will be greatly facilitated by the involvement of faculty and students throughout the University and its affiliated hospitals. Faculty interested in a CMMG appointment should send an application letter and curriculum vitae to the director at 3216 Scott Hall (telephone 313-577-5323).

Faculty Profile: Minoru S. H. Ko, M.D., Ph.D.

Dr. Ko suggests that his approach to investigating these problems may be the best way to discover interesting genes and to begin to analyze their functions. He is making his tools available to the public to help others who may have similar interests. Two of the key technologies that he has developed are the construction of an equalized cDNA library and a PCR-based genetic mapping method for mouse cDNAs. These tools should be applicable to the analysis of interesting genes in other mammalian organisms, including positional cloning of human genetic disease genes.

"Although Dr. Ko's efforts have resulted in the development of important and highly useful tools for these kinds of studies, his primary interests are in the discovery of new knowledge that his tools help to reveal."

The choice of the mouse as a model system is important for the success of Dr. Ko's studies, which are focused on the pre-implantation and peri-implantation stages of early development. For a number of reasons, it is difficult or even impossible to study these stages of human development directly. However, by identifying the genes expressed in the mouse that are essential for these processes, it should be possible to use that information to identify and study the human genes required for the equivalent stages of development.

There are approximately 100,000 genes in the mammalian genome. Dr. Ko estimates that his laboratory will be determining the DNA sequence of more than 30,000 cDNA clones over the next two years, equivalent to about 15 million base pairs of DNA. This effort should result in the identification of around 10,000 new genes, all related to processes in early mammalian development. His studies will make a significant contribution toward the mapping of the mammalian genome and the understanding of the role of specific genes in the developing embryo. Later this fall Dr. Ko will make his database of mouse embryonic genes available to the public through the World Wide Web.

Dr. Ko joined the CMMG at Wayne State University in September of 1992, after earning M.D. (1986) and Ph.D. (1991) degrees at Keio University in Tokyo, Japan, and postdoctoral studies with the Exploratory Research for Advanced Technology (ERATO) project in Tsukuba, Japan. He is currently Assistant Professor (Research) in the CMMG, and is the principal investigator for two NIH grants. In addition, Dr. Ko is the Group Leader for the Genome Asymmetry Group at WSU, which is part of the larger Doi Bioasymmetry Project, ERATO, Research Development Corporation of Japan (JRDC), of Chiba, Japan. The WSU part of this project is funded by the Japanese government for $3,700,00.00 from April 1, 1996, through September 30, 2000. There are currently 17 researchers working in Dr. Ko's laboratory, including 3 M.D./Ph.D., 2 Ph.D., and 2 M.D. scientists. Dr. Ko is also involved in collaborative projects with other researchers and clinicians here at WSU and at other institutions. He welcomes inquiries from others who may wish to study or collaborate with him on the investigation of early mammalian embryonic development.

Representative publications:

Takahashi, N., and Ko, M.S.H. 1993. The short 3'-end region of complementary DNAs as PCR-based polymorphic markers for an expression map of the mouse genome. Genomics 16:161-168.

Takahashi, N. and Ko, M.S.H. 1994. Towards a whole cDNA catalog: an equalized cDNA library from mouse embryos. Genomics 23:202-210.

Ko, M.SH., Wang, X., Horton, J.H., Takahashi, N., Maezaki, Y., and Nadeau, J.H. 1994. Genetic mapping of 40 cDNA clones on the mouse genome by PCR. Mamm. Genome 5:349-355.

Ko, M.S.H. 1995. Equalized cDNA libraries. In: Reverse Transcriptase PCR (Larrick, J.W., and Siebert, P.D., Eds.) Ellis Horwood, London, pp.245-264.

Harada, H., Hashimoto, K., and Ko, M.S.H. 1996. The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J. Invest. Dermatol. 107:41-43.

Yotsumoto, S., Fujiwara, H., Horton, J.H., Mosby, T.A., Wang, X., Cui, Y., and Ko, M.S.H. 1996. Cloning and expression analyses of mouse dystrogylcan gene: Specific expression in maternal decidua at the peri-implantation stage. Human Molec. Genet., in press.

CMMG Activities

Current External Grant Awards to CMMG Faculty

"The CMMG has more than doubled its external grant support with new grants being awarded to six CMMG primary faculty members..."

Finley, Russell L., Jr., NIH, "Isolation of cDNAs for protein interaction networks," $101,090.00 (current budget), $523,003.00 (project period).*

Grossman, Lawrence I., NIH, "Molecular genetics of mammalian cyotchrome c oxidase," $180,273.00 (current budget), $464,190.00 (project period).

Grossman, Lawrence I., NIH, "Molecular evolution of cyotchrome c oxidase," $126,250.00 (current budget), $365,565.00 (project period).

Grossman, Lawrence I., Muscular Dystrophy Association, "COX isoform disruption: A model for mitochondrial myopathy," $95,206.00 (current budget), 255,074.00 (project period).

Ko, Minoru S. H., ERATO/JRDC, "Genome Asymmetry Group - Doi Bioasymmetry Project," $1,195,769.00 (current budget), $3,700,000.00 (project period).*

Ko, Minoru S.H., NIH, "Sequencing and mapping of mouse embryo cDNAs," $298,812.00 (current budget), $848,310.00 (project period).

Ko, Minoru S.H., NIH, "Sequencing and mapping of mouse embryo cDNAs-supplement," $91,159.00 (current budget), $91,159.00 (project period).

Kuivaniemi, Helena, American Heart Association, "Molecular biology of aortic aneurysms," $30,000.00 (current budget), $59,789.00 (project period).*

Kuivaniemi, Helena, Arthritis Foundation (subcontract), "Molecular characterization of Blau Syndrome," $8,500.00 (current budget), $8,500.00 (project period).*

Kurkinen, Markku, NIH, "Matrix proteinases in connective tissue diseases," $165,360.00 (current budget), $491,882.00 (project period).

Lancaster, Wayne D., NIH (subcontract), "Retenoids and intermediate biomarkers for CIN I and CIN II," $84,805.00 (current budget), $307,111.00 (project period).

Lancaster, Wayne D., CDC (substudy), "Class II HLA alleles and clinical course of HIV infection in women," $47,629.00 (current budget), $95,258.00 (project period).

Lancaster, Wayne D., Alaska Native Med. Ctr., "Biological risk factors for cervical cancer in native American women," $27,500.00 (current budget), $27,500 (project period).

Lancaster, Wayne D., USSD, "Carotenoid rich diet," $43,014.00 (current budget), $322,293.00 (project period).*

Murray, Mary, NSF, "Characterization of a translational regulatory particle from Xenopus," $90,000.00 (current budget), $270,000.00 (project period).*

States, J. Christopher, Henry Ford Hospital, "Biopterin and Catecholamines," $4,258.00 (current budget), $37,000 (project period).

States, J. Christopher, NIH, "Minority High School Student Research Apprenticeship Program," $23,000.00 (current budget), $143,500.00 (project period).

Thomas, Robert A., Research Award, "Research stimulation", $6,000.00 (current budget), $6,000.00 (project period).

Tomkiel, John, March of Dimes, "Genetic analysis of centromere functions," $40,000 (current budget), $80,000.00 (project period).*

Tomkiel, John, American Cancer Society, "Analysis of centromere functions," $10,000 (current budget), $10,000.00 (project period).*

Tomkiel, John, NIH, "Genetic analysis of meiotic centromere functions," $96,339.00 (current budget), $525,000.00 (project period).*

Tromp, Gerardus, American Heart Association, "Linkage analysis of intracranial aneurysms to candidate loci," $29,658.00 (current budget), $59,563.00 (project period).*

The CMMG has the privilege and challenge of teaching Medical Genetics to medical students during the second semester of their first year. Medical genetics is both a basic science and a clinical specialty and our goal is to teach it as both. This is reflected in the course faculty which is comprised of both basic scientists and clinicians.

The course, which is co-directed by Mark Paul Johnson, M.D., and Anne Greb, M.S., is organized into 19 lecture hours and six small group sessions. The small group sessions are designed to allow students to integrate and apply information presented in the lectures in a clinically relevant way . These sessions are all led by practicing geneticists and genetic counselors. Also raised throughout the course are some very real ethical and philosophical issues about which we encourage an open discussion.

Overall, students tell us they enjoy the course--especially the clinical application and relevance of basic genetic principles. We are fortunate to have an enthusiastic faculty and would like to thank them for their time and dedication.

Medical Genetics Course Faculty:

Randy Armant, Ph.D. (Obstetrics & Gynecology, Anatomy & Cell Biology), Janice Bach, M.S. (Michigan Department of Public Health, Center for Molecular Medicine & Genetics), Erawati Bawle, M.D. (Pediatrics, Center for Molecular Medicine & Genetics, Medical Genetics & Birth Defects Center, Henry Ford Hospital), Teresa Brady, M.S. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics), Joan Conard, M.S. (Pediatrics, Center for Molecular Medicine & Genetics), Paula Czarnecki, M.S. (Medical Genetics & Birth Defects Center, Henry Ford Hospital, Center for Molecular Medicine & Genetics), Debra Duquette, M.S. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics), Mark Evans, M.D. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics, Pathology), Gerald Feldman, M.D., Ph.D. (Pathology, Center for Molecular Medicine & Genetics, Medical Genetics & Birth Defects Center, Henry Ford Hospital), James Garbern, M.D., Ph.D. (Neurology, Center for Molecular Medicine & Genetics), Anne Greb, M.S. (Center for Molecular Medicine & Genetics), Lawrence Grossman, Ph.D. (Center for Molecular Medicine & Genetics, Internal Medicine), Mark Paul Johnson, M.D. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics, Pathology), Stephanie Kasperski, M.S. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics), Ralph Kramer, M.D. (Obstetrics & Gynecology), Eric Krivchenia, M.S. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics), Helena Kuivaneimi, M.D., Ph.D. (Center for Molecular Medicine & Genetics, Surgery), Jennifer Lampinen, M.S. (Obstetrics & Gynecology, Center for Molecular Medicine & Genetics), Christen Monaghan, Ph.D. (Medical Genetics & Birth Defects Center, Henry Ford Hospital), Vicki Pratt, Ph.D. (Medical Genetics & Birth Defects Center, Henry Ford Hospital), Peggy Rush, M.S. (Medical Genetics & Birth Defects Center, Henry Ford Hospital, Center for Molecular Medicine & Genetics), Kate Sargent, M.S. (Karmanos Cancer Institute, Center for Molecular Medicine & Genetics), Trieu Vo, Ph.D. (Pathology), Yuval Yaron, M.D. (Obstetrics & Gynecology).

CMMG Genetic Counseling Program Approved

The increasing need for genetic counselors arises out of the success of the Human Genome Project which expects to map and sequence the entire human genome and identify disease-causing genes. Genetic counseling helps individuals within families understand their risks for inherited conditions and birth defects so they can make informed decisions. There are only 20 genetic counseling graduate programs worldwide, graduating approximately 100 students each year.

"The M.S. Degree Program in Genetic Counseling is currently accepting applicants for the Fall of 1997..."

The resources of the CMMG and the clinical facilities of the Detroit Medical Center and surrounding metropolitan hospitals will give students a significant opportunity to learn fundamental genetic principles and to gain clinical experiences. Additionally, the diverse population found within our community will provide a unique opportunity to explore how ethnic and cultural differences influence the genetic counseling process and to recruit students from diverse backgrounds into this profession.

In general, CMT is slowly progressive and initially affects the muscles of the distal legs and feet leading to foot deformities and gait abnormalities. Weakness of the hand muscles can occur later in the course of the disorder. CMT can be separated into two major types based on pathophysiology. CMT type 1 (HMSN Type 1), the demyelinating, hypertrophic type, is associated with segmental demyelination, proliferation of Schwann cells, and slowed nerve conduction velocities. CMT type 2 (HMSN Type II), the axonal or neuronal type, is characterized by axonal degeneration and relatively normal nerve conduction velocities. Considerable clinical variation in symptoms among affected individuals, even within the same family, is seen. Onset usually begins within the first two decades. Life expectancy and intelligence are not affected. There is no cure for CMT, although physical and occupational therapy, orthopedic surgery, appropriate splinting and bracing, and supportive footwear all help to alleviate symptoms. It is important that the care of individuals with CMT be managed by a physician familiar with this disease.

Both physiological types of CMT can be further subcategorized based on clinical symptoms and/or mode of inheritance. Additionally, a severe, childhood onset form of CMT is referred to as HMSN Type III (also called Dejerine-Sottas disease), an X-linked form as X-linked HMSN, and forms with additional features as Complex Forms of HMSN. Recent discoveries of specific mutations identified in individuals with CMT has helped to clarify some of this categorization.

In 1991 CMT1A was associated with a submicroscopic duplication on the short arm of chromosome 17. Owing to this duplication on one of the copies of chromosome 17, affected individuals have three copies of this part of the chromosome, instead of the normal two copies. The PMP22 gene was subsequently discovered within this duplicated region. Point mutations within the PMP22 gene have also been identified in patients with CMT1A. The role of the PMP-22 protein is unclear, but appears to be important in the relationship between axons and Schwann cells. Patients with Dejerine-Sottas disease (HMSN, Type III), also can have point mutations within their PMP22 gene. Deletions of the same region duplicated in CMT1A results in hereditary neuropathy with liability of pressure palsies (HNPP). This illustrates how gene dosage can be a critical factor for the function of some genes.

The MPZ gene encodes myelin protein zero (P0), the most abundant structural protein of peripheral nerve myelin, which appears to form links between adjacent myelin layers. The MPZ gene has been mapped to the long arm of chromosome 1. Point mutations within the MPZ gene have been identified in patients with CMT1B and HMSN, Type III. Lastly, connexin 32, a gap junction protein, maps to the long arm of chromosome X. Various mutations within this gene are responsible for X-linked HMSN.

These advances in molecular genetics have clinical applications. The duplication on chromosome 17, which is found in 90% of patients with CMT and a negative family history, can be routinely screened for and is beneficial for diagnostic purposes. In families known to have the duplication of 17p, it is possible to use DNA analysis for presymptomatic and prenatal testing. DNA analysis looking for the deletion of 17p can aid in the diagnosis of HNPP. Also screening for point mutations of Cx32 is routinely available. Although screening for various point mutations of P0 is not routinely available, researchers are still interested in studying these families.

More research needs to be done to identify other causative mutations within these three genes and to identify additional genes perhaps involved in the pathophysiology of CMT. Additionally, detailed information about the function of these genes will be critical in the pursuit of therapeutic strategies such as gene therapy. In several grants funded by the Muscular Dystrophy Association, Drs. John Kamholz and Michael Shy at WSU are developing gene therapy techniques for CMT by using retroviral and adenoviral vectors to introduce genes into the defective Schwann cells in peripheral nerves which cause these diseases. These same investigators, in association with Dr. James Garbern, are investigating mouse models of CMT to study the pathogenesis of the demyelination in CMT. In addition, this group, in association with Dr. Richard Lewis, neurology, has recently identified a novel form of CMT associated with deletions of an additional myelin protein, proteolipid protein (PLP). Finally, clinical studies of the natural history of CMT1A are beginning at WSU, and will be essential to any future trials of new therapeutic interventions, including gene therapy.