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CMMG News

The Center for Molecular
Medicine and Genetics
Volume 2 Issue 1
March 1997

Wayne State University School of Medicine

Enhancing Research and Training in Molecular Medicine and Genetics
1 Message From the Director
2 Robert H. Rownd, Founding Director, Center for Molecular Medicine and Genetics
3 Neuromuscular Gene Therapy Symposium
4 Faculty Profile: Mark I. Evans, M.D.
5 Activities
6 Molecular Methods Course
7 New Faculty
8 Facilities: Adeno Virus Core Facility
9 Feature Article: Genetics of Human Abdominal Aortic Aneurysms
10 Recent Publications from CMMG Faculty

Message From the Director

George Grunberger, M.D.

Welcome to the second volume of the Center for Molecular Medicine and Genetics News, designed to update you on the developments and accomplishments of this University Center. One of the CMMG’s primary missions is to enhance cross-campus collaboration among basic science and clinical investigators as they unravel the molecular and genetic basis of human disease. We wish to extend our invitation to all interested faculty to become appointed in the CMMG as associate or adjunct members. Please call us at 313-577-5323 or send E-mail to CMMG@cmb.biosci.wayne.edu to request an application.

I am saddened to report the death of Dr. Robert H. Rownd, Ph.D., Founding Director of the CMMG, whose messages opened the two previous issues of the CMMG News. Dr. Rownd was a distinguished scientist and accomplished administrator, and the CMMG and Wayne State University will miss him. An article highlighting Dr. Rownd'’s career begins on page 2.

The CMMG sponsored a highly acclaimed Symposium on Genetics, Evolution, and Disease last October in honor of the retirements of Professors Jack and Sandy Miller. Continuing in that tradition, the CMMG will cosponsor, with the department of neurology, a Symposium on Neuromuscular Gene Therapy on March 21 (page 3). Then in October, the CMMG will sponsor a two-day Symposium on Frontiers in Molecular Medicine, in honor Dr. Rownd. An international group of distinguished scientists has been invited to participate, and details will be made available closer to the date of the symposium (see page 5).

The CMMG is privileged to count Mark I. Evans, M.D., as one of its members. A faculty profile of Dr. Evans, Director of the Division of Reproductive Genetics in the Department of Obstetrics and Gynecology, is on page 4. Five new faculty members (page 7) who hold primary appointments in clinical departments in the School of Medicine or its affiliated hospitals have been appointed as adjunct or associate members of the CMMG during the past six months, which brings the current total to 48 faculty members in the CMMG.

"We wish to extend our invitation to all interested faculty to become appointed in the CMMG as associate or adjunct members. Please call us at 313-577-5323 or send E-mail to CMMG@cmb.biosci.wayne.edu to request an application."

The CMMG will offer a new course on Methods and Concepts in Molecular Medicine and Genetics beginning this Fall. This course will emphasize recombinant DNA technology and molecular genetics and their applications to modern medicine (page 6). Previous issues of the CMMG News have described our Macromolecular Core Facility and Shared Biocomputing Facility. The CMMG is expanding its services by opening a new Adenoviral Vector Core Facility in the Elliman Building (page 8). The feature article of this edition of the CMMG News is on the "Genetics of Human Abdominal Aortic Aneurysms," a field under study by two CMMG faculty members, Helena Kuivaniemi, M.D., Ph.D., and Gerard Tromp, Ph.D. (page 9).

The CMMG is progressing well in its research, educational, and service programs. As Dr. Rownd emphasized in previous issues of the CMMG News, 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.


Robert H. Rownd, Ph.D., Founding Director, Center for Molecular Medicine and Genetics

Robert H. Rownd, Professor and Founding Director of the Center for Molecular Medicine and Genetics at Wayne State University School of Medicine, died on January 4, 1997, of pancreatic cancer at the age of 59.

Bob Rownd was born in Chicago on July 4, 1937. Later, his three young children would believe the fireworks displays were in honor of his birthday. He earned his B.S. in Chemistry from St. Louis University in 1959, and received that institution’s Alumni Merit Award in 1984. Bob received an A.M. in Medical Sciences in 1961 and a Ph.D. in Biophysics in 1964, both from Harvard University. His graduate work in the laboratory of Paul Doty included early studies on the physical-chemical properties of DNA, and the demonstration of the DNA nature of bacterial antibiotic resistance plasmids.

Following postdoctoral training with Sydney Brenner in Cambridge, England, and with Jacques Monod in Paris, France, Bob accepted a faculty position at the University of Wisconsin, Madison, in the Department of Biochemistry and the Laboratory of Molecular Biology in 1966. Bob received a USPHS Career Development Award in 1968, and a NIH Research Grant that was continuously funded for 26 years. Bob was an energetic and tireless scientist and administrator, and became chairman of the Laboratory of Molecular Biology at Wisconsin in 1970. He was Program Director of the USPHS Training Grant in Molecular Biology at Wisconsin from 1970 through 1979, which served in the development of many talented graduate students. He became Full Professor at Wisconsin in 1973.

Bob accepted the Chair of the newly formed Department of Molecular Biology at the Northwestern University Medical and Dental Schools in Chicago in 1981, where he recruited a faculty of highly enthusiastic and successful young scientists. He was the first John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern and held the Chair until 1991. Bob served Northwestern as Director of the Interdisciplinary Doctoral Program in Molecular and Cellular Biology and as Director of the Combined M.D./Ph.D. Program. He was Co-Director of the Training Grant in Cellular and Molecular Biology, and Program Director of the Medical Scientist Training Program Grant, both awarded by USPHS to Northwestern largely as a result of his efforts.

In 1990, Bob became Director and Professor of the Center for Molecular Biology at Wayne State University, and Interim Chair of the Department of Molecular Biology and Genetics in 1993. He merged those two units into the new Center for Molecular Medicine and Genetics at Wayne State in 1994, and served as its Director and Professor until his death.

Bob was an innovative and pioneering scientist, describing the first example of multiple, tandemly repeated gene amplification in bacteria, and publishing the first restriction map of a transmissible antibiotic resistance plasmid. He made many contributions in DNA replication control and its coordination with cell growth and division, publishing approximately 150 articles, reviews, and book chapters. Recently, Bob had begun to shift his interests into more direct applications in molecular medicine such as gene therapy. In addition to his teaching, research, and administrative efforts, Bob also served on multiple editorial boards, study sections, and conference organizing committees. He was a member of the Editorial Board of the Journal of Bacteriology from 1975 to 1981, and was Editor from 1981 through 1990. Bob directed the Ph.D. dissertations of 20 graduate students, trained 37 postdoctoral fellows, and provided opportunities for many undergraduate students and visiting faculty members to study in his laboratory.

Bob had an affinity for other cultures, and enjoyed training many international students in his lab. Many holidays were spent hosting foreign students in the Rownd home. He and his wife Rosalie seized opportunities to travel the world to various scientific conferences and made many new friends along the way. Bob was also an avid tennis player and long time patron of the symphony and opera. In addition to his wife of 37 years, Rosalie, he is survived by his three children, Jennifer, Robert, Jr., and David, and two grandchildren, Meagan and Kelly.

The original version of this article appeared in the March issue of the ASM News.


CMMG to Cosponsor Neuromuscular Gene Therapy Symposium March 21, 1997

The CMMG and the Department of Neurology will cosponsor a one-day symposium on Advances in Gene Therapy for Neuromuscular Disease. A group of distinguished neurogeneticists will make research presentations from 8:00 AM to 4:15 PM on Friday, March 21, 1997, in the Blue Auditorium of Scott Hall.

For further details and free registration for the Symposium, contact Ms. Izabella Gavric by E-mail (igavric@med.wayne.edu), by phone (313-577-1689), or by using the form page posted on the World Wide Web (URL http://cmmg.biosci.wayne.edu/asg/nmgtsymposium.html).

Invited Speakers:

George Karpati, M.D., I.W. Killam Chair of Neurology, Director of Neuromuscular Research Laboratories, Montreal Neurological Institute, McGill University, Montreal, Canada, "Gene therapy for Duchenne Muscular Dystrophy -1997: Should we be bullish or bearish ?"

Jon Wolff, M.D., Professor of Pediatrics, Director of Biochemical Genetics, University of Wisconsin, Madison, Wisconsin, "New approaches for gene transfer."

Paula Clemens, M.D., Assistant Professor of Neurology and Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, "Large capacity adenoviral vectors for dystrophin delivery."

Hansell Stedman, M.D., Ph.D., Associate Professor of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, "Systemic administration of genes by adenoviral vectors."

John Kamholz, M.D. Ph.D., Associate Professor of Neurology and the Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, "Introduction to gene therapy in neuromuscular Disease."

Michael E. Shy, M.D., Associate Professor of Neurology and the Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, "Approaches to gene therapy in Charcot Marie Tooth Disease."

Gyula Acsadi, M.D., Instructor, Departments of Pediatric Neurology and the Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, "Approaches to gene therapy in diseases of motor neurons."

George Grunberger, M.D., Professor of Internal Medicine, Professor and Interim Director, Center for Molecular Medicine and Genetics, Director, Center for Clinical Research, Director, Diabetes Program at Wayne State University/Detroit Medical Center, Detroit, Michigan, "Opening of symposium."

Robert Lisak, M.D., Professor and Chair of Neurology, Professor of Immunology and Microbiology, Wayne State University, Detroit, Michigan, "Closing of symposium."



Faculty Profile: Mark I. Evans, M.D.

The pioneering research efforts at Wayne State University in the area of prenatal diagnosis and fetal therapy will be further expanded by the creation of an endowed chair for fetal diagnosis and therapy in Obstetrics and Gynecology. The Charlotte Bush Failing Chair was recently awarded to Mark I. Evans, M.D., and continues a long-standing generosity of the Failing family towards Hutzel Hospital and the Detroit Medical Center. It also highlights the successful and prominent career of Dr. Evans who is Professor, Vice Chairman, and Vice Chief of the Department of Obstetrics and Gynecology and Professor of the Department of Pathology as well as the Center for Molecular Medicine and Genetics. Dr. Evans’s role in the CMMG has recently expanded with his appointment as Chief, Division of Human Genetics. Dr. Evans came to Wayne State University in 1984 after completing a genetics fellowship at the National Institutes of Health. As a fellow, he devised a medical therapy for the first prevention of a birth defect by preventing genital masculization in female fetuses with congenital adrenal hyperplasia.

Dr. Evans is founding Director of both the Division of Reproductive Genetics as well as the Center for Fetal Diagnosis and Therapy here at Wayne State University. Over the past decade these programs have made major contributions in the development of fetal surgical, medical, and genetic therapies and are recognized internationally. The most recent major breakthrough in fetal therapy was recently published by Dr. Evans and his colleagues in the New England Journal of Medicine in December, 1996. Working with Dr. Alan Flake and others at Children’s Hospital of Michigan, their report describes the first successful in utero treatment of a fetus with severe combined immune deficiency syndrome (SCIDS), or a "bubble baby", with donor hematopoietic stem cell transplantation. Engraphment of donor cells at a specific time during fetal development virtually eliminates the complication of graft vs. host disease and holds much hope for curing fetuses with certain genetic conditions.

"The Charlotte Bush Failing Chair of Obstetrics and Gynecology was recently awarded to Mark I. Evans, M.D."

In addition to the use of donor hematopoietic stem cells to treat genetic conditions in fetuses, Dr. Evans and his colleagues have developed many other novel in utero diagnostic and therapeutic techniques to help families facing the birth of a child with a serious medical condition. Patients travel to The Detroit Medical Center from all over the country to obtain his help in the management of their multifetal pregnancies. He developed the procedure of obtaining a fetal muscle sample for specific diagnostic studies in fetuses at risk for Duchenne Muscular Dystrophy. Other areas of expertise he and his associate, Mark Paul Johnson, M.D., have developed include the use of percutaneous shunts to treat fetal obstructive uropathies and pleural effusions as well as endoscopic visualization of the fetus for diagnostic purposes and surgical interventions.

Drs. Evans and Johnson currently serve as Co-Presidents of the International Fetal Medicine and Surgery Society. Dr. Evans was awarded the Wayne State University Career Development Chair in 1989, the Board of Governors Faculty Recognition Award in 1994, and was recently elected to the Academy of Scholars of Wayne State University. He has served on numerous hospital, university, national, and international committees. Author of over 800 publications, including 18 textbooks, Evans is the editor of the Journal of Fetal Diagnosis and Therapy, and also serves on the editorial boards of several journals including Prenatal Diagnosis, the American Journal of Medical Genetics, and the Journal of the Society for Gynecological Investigation. Dr. Evans has two NIH research grants funded by the Institute for Child Health and Human Development (NICHD).

As an obstetrician geneticist, Dr. Evans directs the provision of prenatal diagnostic and genetic counseling services to over 2500 patients each year. He also runs a reproductive genetics fellowship program. He is currently leading the development of a new academic program at Wayne State University called the Human Genetics Program (HGP). This program will further expand the research efforts and clinical services in human genetics to other medical specialties throughout the Medical Center and University. Dr. Evans’s contributions in the areas of prenatal diagnosis, fetal therapy, and human genetics are certain to continue.

Representative publications:

Evans, M.I., Chik, L., O'Brien, J.E., Dvorin, E., Johnson, M.P., Krichenia, E., and Sokol, R.J. 1996. Logistic regression generated probability estimates for Trisomy 21 outcomes from serum AFP and Beta-HCG: Simplification with increased specificity. J. Matern. Fetal Med. 5:1-6.

Flake, A.W., Roncarolo, M.G., Puck, J.M., Almieda-Porada, G., Evans, M.I., Johnson, M.P., Abella, E.M., Harison, D.D., and Zanjani, E.D. 1996. Treatment of X-linked severe combined immunodeficiency by in-utero transplantation of paternal bone-marrow. New Eng. J. Med. 335(24):1806-1810.

Evans, M.I., Johnson, M.P, and Moghissi, K.S. 1997. Invasive Outpatient Procedures. Lippincott/Raven Press, Philadelphia.


CMMG Activities

CMMG to Sponsor Symposium: Frontiers in Molecular Medicine, October 3-4, 1997

The CMMG will sponsor a two-day Symposium: Frontiers in Molecular Medicine, in honor of the late Robert H. Rownd, Ph.D., Founding Director of the CMMG. An international group of scientists will make research presentations on Friday, October 3, 1997, and on Saturday, October 4, 1997, in the Blue Auditorium of Scott Hall. There will be a deli lunch and poster session on Saturday, October 4, 1997.

Further details as they become available will be posted on the World Wide Web (URL http://cmmg.biosci.wayne.edu/symposium.html).

CMMG to Sponsor Methods and Concepts in Molecular Medicine and Genetics Course

The CMMG will offer a new course, Methods and Concepts in Molecular Medicine and Genetics, to start in the Fall of 1997, and continue for the remainder of the school year. The course will be taught primarily by CMMG faculty and will emphasize recombinant DNA biotechnology and molecular genetics and their application to modern medicine. Sample topics include recombinant DNA basics, analysis of cloned genes, PCR, detection of mutations, human molecular genetics, gene therapy, transgenics, and computer applications. The main focus will be to provide medical researchers not primarily trained in molecular biology with a working knowledge to both follow the current literature and apply molecular tools in their own research. The course, which will be available for CME credit, will be held during a two-hour late afternoon or evening block every other week. Course materials will consist of handouts prepared by the staff as well as a text. Watch this space for additional details. Further information is available from Prof. L. I. Grossman (313-577-5326; lg@cmb.biosci.wayne.edu).

"This course will emphasize recombinant DNA technology and molecular genetics and their applications to modern medicine."

CMMG Welcomes New Faculty Members

The following faculty members have recently been appointed to adjunct or associate faculty positions in the CMMG:

Gyula Acsadi, M.D. (pediatric neurology), Joan V. Conard, M.S. (pediatrics), Li Li, Ph.D. (internal medicine), Peggy W. Rush, M.S. (Henry Ford Hospital), Assia Shisheva, Ph.D. (physiology).

CMMG Adeno Virus Core Facility

The CMMG Adenoviral Vector Core Facility, which will be located in the Elliman Building, will serve three purposes. First, the facility will make available to Wayne State University scientists several recombinant adenoviral vectors (AVR), including those expressing the reporter genes lacZ (AdCMVlacZ), luciferase (AdCMVlux), and herpes thymidine kinase (AdCMVtk). These vectors have been shown to be useful for determining the ability and efficiency of recombinant adenovirus to transduce exogenous genes into specific cell types, both in vitro and in vivo. Second, the facility will produce new AVR, expressing genes of interest, for Wayne State University researchers. The facility will provide the researcher with the adenoviral transfer vector into which the gene of interest must be cloned, and will then perform the steps (co-transfection of 293 cells, identification of recombinant plaques, plaque purification, and large scale viral isolation) necessary to produce the new recombinant virus. Third, the facility staff will provide technical assistance and/or advice for researchers using or contemplating using recombinant defective adenoviral vectors. This advice will include the feasibility of using recombinant defective adenoviral vectors, and methods for viral delivery and detection of adenoviral-mediated gene transfer in vitro and in vivo. The Elliman adenoviral vector core will thus assist Wayne State University researchers in the use of recombinant defective adenoviral vectors in order to facilitate their use in basic and gene therapy research.

WSU scientists who would like to participate in development of adenoviral vectors for their research projects should contact the director of the facility, John Kamholdz, M.D., Ph.D., at 313-577-0925, or jkamholz@cmb.biosci.wayne.edu.

In addition to the Adenoviral Vector Core Facility, the CMMG maintains a Macromolecular Core Facility for synthesis of oligonucleotides and DNA sequencing, and a Shared Biocomputing Facility for analysis of molecular sequence data. For further information about the Macromolecular Core Facility, please contact Michael Hagen, Ph.D., at 313-577-1178, or mhagen@cmb.biosci.wayne.edu . For further information about the Shared Biocomputing Facility, please contact David Womble, Ph.D., at 313-577-2374, or dwomble@cmb.biosci.wayne.edu . Additional information about CMMG facilities, services, and programs is available at our World Wide Web site, http://cmmg.biosci.wayne.edu/ .


Genetics of Human Abdominal Aortic Aneurysms

Abdominal aortic aneurysms are slowly developing balloon-like swellings in the wall of the aorta which rupture when they reach a critical size. Rupture of aortic aneurysms is the 13th leading cause of death in the United States, killing approximately 15,000 individuals every year. It is estimated 1-2% of the population silently harbor aneurysms in their aorta. In some cases the aneurysm is detected on an ultrasound examination of the abdomen done for other reasons, or as part of a screening test for individuals with a positive family history. Early detection and elective surgical repair of aortic aneurysms not only greatly lowers mortality and morbidity, but also is more cost effective than repairing a ruptured aortic aneurysm.

Genetic factors are thought to play an important role in the underlying cause of aortic aneurysms. Several studies have demonstrated that aneurysms frequently run in families, even when not associated with well-recognized inherited syndromes such as Marfan syndrome or Ehlers-Danlos syndrome, type IV. Empiric data suggest the risk for individuals with an affected first degree relative of also developing an aortic aneurysm is 11.6 times greater than for individuals without a positive family history. The genetic contribution to the etiology of aortic aneurysm is not the same in all families. Multifactorial inheritance is the likely cause in some families, whereas in other families, one or a few genes play a major role in the development of aortic aneurysms. In these families the risk is 50% for other family members to inherit the susceptibility gene(s). Of course, in other families, genetic factors play little or no role in the determination of aortic aneurysms. Genetic heterogeneity is the term used to describe the occurrence of numerous etiologies for one disorder and is characteristic of most medical conditions.

Once the genetic component involved in the etiology of aortic aneurysms is identified at the molecular level, a DNA test could identify individuals with a genetic predisposition. These individuals would then be candidates for increased surveillance with diagnostic tests such as ultrasonography and, if necessary, elective surgery to remove the aneurysm. Early detection of aortic aneurysms increases the chance for an effective treatment and subsequent long-term survivorship.

Researchers at Wayne State University are attempting to locate the susceptibility gene(s) for abdominal aortic aneurysms in human chromosomes using DNA linkage analysis. Subsequently, candidate genes will be analyzed for specific mutations. S. Helena Kuivaniemi, M.D., Ph.D., and Gerardus C. Tromp, Ph.D., of the CMMG are leading this research effort. They are also studying the genetic causes of intracranial aneurysms. Both of these research efforts depend on the participation of families who have at least three affected living members with aortic or intracranial aneurysms who are willing to give a blood sample for DNA linkage analysis. In collaboration with the Departments of Surgery and Neurosurgery, the CMMG is recruiting families who are interested in participation in this important study. If you are aware of such families, please contact Dr. Helena Kuivaniemi (577-8733 or hkuivan@cmb.biosci.wayne.edu.) or Anne Greb, M.S., a genetic counselor working on the project (577-6298 or agreb@cmb.biosci.wayne.edu).

As progress continues in the Human Genome Project, the gene(s) involved in many common adult onset conditions such as aortic aneurysms will be identified. The era of screening individuals with a genetic predisposition to a particular disorder in order to provide targeted screening and prophylactic therapies is upon us. The CMMG is proud to participate in research efforts in this arena.

Representative publications:

Jaakkola. P., Kuivaniemi, H., Partanen, K., Tromp, G., Liljestrom, B., and Ryynanen, M. 1996. Familial abdominal aortic aneurysms: screening of 71 families of patients with abdominal aortic aneurysms. Eur. J. Surg. 162:611-617.

Kuivaniemi, H., Shitkata, H., Utsumi, N., and Tromp, G. 1996. Mutations in Type III procollagen gene as causes of heritable disorders. Conn. Tiss. 28:205-213.

Kuivaniemi, H., Watton, S.J., Price, S.J., Zhu, Y., Gatalica, Z., and Tromp, G. 1996. Candidate genes for abdominal aortic aneurysms. Annals N.Y. Acad. Sci. 800:186-197.

Prockop, D.J., Kuivaniemi, H., and Tromp, G. 1997. Heritable disorders of connective tissue. In: The Harrison's Textbook of Internal Medicine 14th Edition (Isselbacher, K.J., et al., eds.). McGraw-Hill, Inc., New York.

Ronkainen, A., Hernesniemi, J., Puranen, M., Niemitukia, L., Vanninen, R., Ryynanen, M., Kuivaniemi, H., and Tromp, G. 1997. Familial intracranial aneurysms: MR angiography screening of asymptomatic first-degree relatives reveals an intracranial aneurysm in 9% of screened subjects. The Lancet 349:380-384.

Tromp, G., Kuivaniemi, H., Raphael, S., Ala-Kokko, L., Christiano, A., Considine, E., Dhulipala, R., Hyland, J., Jokinen, A., Kivirikko, S., Korn, R., Madhatheri, S., McCarron, S., Pulkkinen, L., Punnett, H., Shimoya, K., Spotila, L., Tate, A., and Williams, C.J. 1996. Genetic linkage of familial granulomatous inflammatory arthritis skin rash and uveitis to chromosome 16. Am. J. Hum. Genet. 59:1097-1107.


Recent Publications from CMMG Faculty

Acsadi, G., Jani, A., Lochmueller, H., Huard, J., Massie, B., Prescott, S.,Simoneau, M., Petrof, B., and Karpati, G. 1996. Dystrophin expression in musclesof mdx mice after Adenovirus-mediated in vivo gene transfer. Human GeneTherapy 7:129-140.

Anastasiadis, P.Z., States, J.C., Imerman, B.A., Louie, M.C., Kuhn, D.M. and Levine, R.A. 1996. Mitogenic Effects of Tetrahydrobiopterin in PC12 Cells. Molecular Pharmacology 49:149-155.

Benbow, U., Butticé, G., Nagase, H., and Kurkinen, M. 1996. Characterization of the 46-kDa intermediates of matrix metalloproteinase-3 (stromelysin-1) obtained by site-directed mutation of phenylalanine-83. J. Biol. Chem. 271:10715-10722.

Butticé, G., Duterque-Coquillaud, M., Basuyaux, J.P., Carrere, S., Kurkinen, M., and Stehelin, D. 1996. Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene 13:2297-2306.

Carlock, L., Vo, T., Lorincz, M., Walker, P.D., Bessert, D., Wisniewski, D., and Dunbar, J. 1996. Variable subcellular localization of a neuron-specific protein during NTera2 differentiation into post-mitotic neurons. Mol. Brain Res. 42:202-212.

Cher, M.L., Abernathy, B.B., McConnell, J.D., Zimmern, P.E., Lin, V.K. 1996. Smooth muscle myosin heavy-chain isoform expression in bladder-outlet obstruction. World J. Urol. 14:295.

Cher, M.L., Bova, G.S., Moore, D.H., Small, E.J., Carroll, P.R., Pin, S.S., Epstein, J.I., Isaacs, W.B., Jensen, R.H. 1996. Genetic alterations in untreated metastases and androgen independent prostate cancer detectedby comparative genomic hybridization and allelotyping. Cancer Research 56:3091.

Chiu, C-H., Schneider, H., Sampaio, I., Schneider, M.P.C., Slightom, J.L., Gumucio, D., and Goodman, M. 1996. Reduction of two functional gamma-globin genes to one: an evolutionary trend in New World monkeys (Infraorder Platyrrhini). Proc. Natl. Acad. Sci. USA 93:6510-6515.

Crowley, J.J., and Bawle, E.V. 1996. Small bowel malrotation in each of a pair ofidentical twins. Pediatr. Radiol. 26:127-128.

Czarnecki, P., Lacombe, D., and Weiss, L. 1996. Toriello-Carey Syndrome: Evidence for X-linked inheritance. Am. J. Med. Genet. 65:291-294.

D'Sa, C.M., Arthur, R.A., Jr., and Kuhn, D.M. 1996. Expression and deletion mutagenesis of tryptophan hydroxylase fusion proteins: delineation of the enzyme catalytic core. J. Neurochem. 67:917-926.

D'Sa, C., Arthur, R.E., Jr., States, J.C., and Kuhn, D.M. 1996. Tryptophan hydroxylase: Cloning and expression of the rat brain enzyme in mammalian cells. J. Neurochem. 67:900-906.

Durham, HD, Lochmuller, H., Jani A., Acsadi, G., Massie, B., Karpati, G. 1996. Toxicity of replication-defective Adenoviral recombinants in dissociated cultures of nervous tissue. Exp. Neurology 140:14-20.

Eadara, J.K., Hadlock, K.G. and Lutter, L.C. 1996. Chromatin structure and factor site occupancies in an in vivo-assembled transcription elongation complex. Nucleic Acids Res. 24:3887-3895.

Eadara, J.K. and Lutter, L.C. 1996. Determination of occupancies of the SPH and GT-IIC transcription factor binding motifs in SV40: evidence for two forms of transcription elongation complex. Virology 223:120-131.

Evans, M.I., Chik, L., O'Brien, J.E., Dvorin, E., Johnson, M.P., Krichenia, E., and Sokol, R.J. 1996. Logistic regression generated probability estimates for Trisomy 21 outcomes from serum AFP and bHCG: Simplification with increased specificity. J. Matern. Fetal Med. 5:1-6.

Finley Jr., R.L. and Brent, R. 1996 Two-hybrid analysis of geneticregulatory networks. In: The yeast two-hybrid system (Bartel, P.L., andFields, S., eds.). Oxford University Press, Oxford, England.

Finley Jr., R.L., Thomas, B.J., Zipursky, S.L., and Brent, R. 1996.Isolation of Drosophila Cyclin D, a protein expressed in the morphogeneticfurrow before entry into S phase. Proc. Natl. Acad. Sci. U.S.A.93:3011-3015.

Evans, M.I., Johnson, M.P., and Moghissi, K.S. 1997. Invasive Outpatient Procedures. Lippincott/Raven Press, Philadelphia.

Fitzgerald, J.T., Anderson, R.M., Funnell, M.M., Arnold, M.S., Davis, W.K., Aman, L.C., Jacober, S.J., and Grunberger, G. 1997. Differences in the impact of dietary restrictions on African Americans and Caucasians with NIDDM. Diab. Educator 23:41-47.

Flake, A.W., Roncarolo, M.G., Puck, J.M., Almieda-Porada, G., Evans, M.I., Johnson, M.P., Abella, E.M., Harison, D.D., and Zanjani, E.D. 1996. Treatment of X-linked severe combined immunodeficiency by in-utero transplantation of paternal bone-marrow. New Eng. J. Med. 335(24):1806-1810.

Gervasi, D.C., Raz, A., Dehem, M., Yang, M., Kurkinen, M., and Fridman, R. 1996. Carbohydrate-mediated regulation of matrix metalloproteinase-2 activation in normal human fibroblasts and fibrosarcoma cells. Biochem. Biophys. Res. Commun. 228:530-538.

Goodman, M. 1996. Epilogue: A personal account of the origins of a new paradigm. Mol. Phylogenet. Evol. 5:269-285.

Grossman, L.I., and Shoubridge, E.A. 1996. Invited article: Human mitochondrial genetics and disease. BioEssays 18:983-991.

Jaakkola. P., Kuivaniemi, H., Partanen, K., Tromp, G., Liljestrom, B., and Ryynanen, M. 1996. Familial abdominal aortic aneurysms: screening of 71 families of patients with abdominal aortic aneurysms. Eur. J. Surg. 162:611-617.

Johnson, R.M., Buck, S., Chiu, C-H., Schneider, H., Sampaio, I., Gage, D.A., Shen, T-L., Schneider, M.P.C., Gumucio, D.L., and Goodman, M. 1996. Fetal globin expression in New World monkeys. J. Biol. Chem. 271: 14684-14691.

Keeney, S., Giroux, C.N., and Kleckner, N. 1997. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88:375-384.

Kramer, J.A. and Krawetz, S.A. 1996. Nuclear matrix interactions within the sperm genome. J. Biol. Chem., 271(20):11619-11622.

Kramer, J.A., Singh, G.B.and Krawetz, S.A. 1996. Computer assisted search for sites of nuclear matrix attachment. Genomics 33:305-308.

Kuhn, D.M. and Arthur, R.E., Jr. 1996. Inactivation of brain tryptophan hydroxylase by nitric oxide. J. Neurochem. 67:1072-1077.

Kuivaniemi, H., Shitkata, H., Utsumi, N., and Tromp, G. 1996. Mutations in Type III procollagen gene as causes fo heritable disorders. Conn. Tiss. 28:205-213.

Kuivaniemi, H., Watton, S.J., Price, S.J., Zhu, Y., Gatalica, Z., and Tromp, G. 1996. Candidate genes for abdominal aortic aneurysms. Annals N.Y. Acad. Sci. 800:186-197.

Lancaster, W.D., Campione-Picarrdo, J. 1997. Viral agents. In: Encyclopedia of Cancer (Bertino, J.R., ed.),. Academic Press, New York, pp. 1969-1982.

Lyons, H., Bawle, E., Blodgette, J., and Klein, M. 1996. Achalasia and deficient tearproduction in monozygotic twins. Int. Pediatr. 11:103-105.

Lutter, L C., Halvorson, H.R., and Calladine, C.R. 1996. Topological measurement of protein-induced DNA bend angles. J. Mol. Biol. 261:620-633.

Maki, T., Gruver, E.J., Davidoff, A.J., Izzo, N., Toupin, D., Colucci, W., Marks, A.R., and Marsh, J.D. 1996. Regulation of calcium channel expression in neonatal myocytes by catecholamines. J. Clin. Invest. 97:656-663.

Moshier, J.A., Mutchnick, M.G., Doscescu, J., Holtz, T., Akkary, S., Mahakala, K., Skunca, M., Merline, J., and Naylor, P. 1996. Thymosine-a1, but not interferon-a, specifically inhibits anchorage-independent growth of Hepatitis B viral transfected HepG2 cells. J. Hepatol. 25:814-820.

Moshier, J.A., Skunca, M., Wu, W., Boppana, S.M., Rauscher, F.J., and Doscescu, J. 1996. Regulation of ornithine decarboxilase gene expression by the Wilms' tumor suppressor WT1. Nucl. Acids Res. 24:1149-1157.

Myrand, S.P., Topping, R.S., and States, J.C. 1996. Stable transformation of xeroderma pigmentosum group A cells with an XPA minigene restores normal DNA repair and mutagenesis of UV-treated plasmids. Carcinogenesis 17:1907-1919.

Naylor, P.H., Smith, M.R., Mutchnick, M.G., Naylor, C.W., Sonnek, D., Burse, L. Dosescu, J., Skunca, M., Khilani, S.D., Goldstein, A.L., and Moshier, J.A. 1996. Thymosin-a1 does not promote growth or oncogene transformation. Int. J. Immunopharmac. 18:321-327.

Oko, R., Korley, R., Murray, M.T., Hecht, N.B., and Hermo, L. 1996. The germcell specific DNA and RNA-binding proteins p48/52 are expressed at specificstages of male germ cell development and are present in the chromatoid body. Mol. Reprod. Devel. 44:1-13.

Petrof, B.J., Acsadi, G., Bourdon, J., Matusiewicz, N., Yang, L. 1996. Plasmid-mediated in vivo gene transfer to rat diaphragm: Phenotypic and immunologic factors affect gene transfer efficiency and stability. Am. J. Physiol. 270:1023-1030.

Prockop, D.J., Kuivaniemi, H., and Tromp, G. 1997. Heritable disorders of connective tissue. In: The Harrison's Textbook of Internal Medicine 14th Edition (Isselbacher, K.J., et al., eds.). McGraw-Hill, Inc., New York.

Quan, T.H., and States, J.C. 1996. Preferential DNA Damage in p53 gene by benzo(a)pyrene metabolites in CYP1A1-expressing xeroderma pigmentosum group A cells. J. Molecular Carcinogenesis 16:32-43.

Quintero, R.A., Romero, R., Reich, H., Goncalves, L., Johnson, M.P., Carreno, C., Evans, M.I. 1996. In utero percutaneous umbilical-cord ligation in the management of complicated monochorionic multiple gestations. Utrasound Obst. Gynecol. 8:48-52.

Qureshi, F., Jacques, S.M., Seifman, B., Quintero, R., Evans, M.I., Smith, C., Johnson, M.P. 1996. In utero fetal urine analysis and renal histology do correlate with outcome in fetal obstructive uropathies. Fetal Diag. Therapy 11:306-312.

Ritchie, R.H., and Marsh, J.D. 1997. Cardiovascular adrenergic and muscarinic cholinergic receptors. In: Cardiology Looseleaf (Parmley, W., and Chatterjee, K., eds.) Lippincott-Raven, New York.

Ronkainen, A., Hernesniemi, J., Puranen, M., Niemitukia, L., Vanninen, R., Ryynanen, M., Kuivaniemi, H., and Tromp, G. 1997. Familial intracranial aneurysms: MR angiography screening of asymptomatic first-degree relatives reveals an intracranial aneurysm in 9% of screened subjects. The Lancet 349:380-384.

Sawai, T., Uzuki, M., Harris, E.D., Jr., Kurkinen, M., Trelstad, R.L., and Hayashi, M. 1996. In situ hybridization of stromelysin mRNA in the synovial biopsies from rheumatoid arthritis. Tohoku J. Exp. Med. 178:315-330.

Seelan, R.S., Gopalakrishnan, L., Scarpulla, R.C., and Grossman, L.I. 1996. Cytochrome c oxidase subunit VIIa liver isoform: Characterization and identification of promoter elements in the bovine gene. J. Biol. Chem. 271:2112-2120.

Shridhar, V., Rivard, S., Shridhar, R., Mullins, C., Bostick, L., Sakr, W., Grignon, D., Miller, O.J., and Smith, D.I. 1996. A gene from human chromosomal band 3p21.1 encodes a highly conserved arginine-rich protein and is mutated in renal cell carcinomas. Oncogene 12:1931-1939.

Shridhar, R., Shridhar, V., Rivard, S., Siegfried, J.M., Pietraszkiewicz, H., Ensley, J., Pauley, R., Grignon, D., Sakr, W., Miller, O.J., and Smith, D.I. 1996. Mutations in the arginine-rich protein gene in lung, breast, and prostate cancers, and in squamous cell carcinoma of the head and neck. Cancer Res. 56:5576-5578.

Shy, M., Jun, Y., Feltri, M.L., Wrabetz, L., Kamholz, J., and Scherer, S. 1996. Axon-Schwann cell interactions regulate the expression of c-jun in Schwann cells. J. Neurosci.Res. 43:511-523.

Slightom, J.L., Bock, J.H., Tagle, D.A., Gumucio, D.L., Goodman, M., Stojanovic, N., Jackson, J., Miller, W., and Hardison, R. 1997. The complete sequences of the galago and rabbit b-globin Locus Control Regions: Extended sequence and functional conservation outside the cores of DNase hypersensitive sites. Genomics 39:90-94.

Srinivas, P.R., Deutsch, D.D., Mathews, S.T., Goustin, A.S., Leon, M.A., and Grunberger, G. 1996. Recombinant human serum a2-HS glycoprotein inhibits insulin-stimulated mitogenic pathway without affecting metabolic signalling in Chinese Hamster Ovary cells overexpressing the human insulin receptor. Cell. Signal. 8:567-573.

States, J.C., and Myrand, S.P. 1996. Splice Site Mutations in a Xeroderma Pigmentosum Group A Patient with Delayed Onset of Neurological Disease. Mutation Research 363:171-177.

States, J.C., and Reed, E. 1996. Enhanced XPA mRNA levels in cisplatin-resistant human ovarian cancer are not associated with XPA mutations or gene amplification. Cancer Letters 108:233-237.

Tafas, T., Cuckle, H., Nasr, S., Krichenia, E.L., Resvani, E., and Evans, M.I. 1996. An automated image analysis method for the measurement of neutrophil alkaline phosphatase in the prenatal screening of Down syndrom. Fetal Diag. Therapy 11:254-249.

Tromp, G., Kuivaniemi, H., Raphael, S., Ala-Kokko, L., Christiano, A., Considine, E., Dhulipala, R., Hyland, J., Jokinen, A., Kivirikko, S., Korn, R., Madhatheri, S., McCarron, S., Pulkkinen, L., Punnett, H., Shimoya, K., Spotila, L., Tate, A., and Williams, C.J. 1996. Genetic linkage of familial granulomatous inflammatory arthritis skin rash and uveitis to chromosome 16. Am. J. Hum. Genet. 59:1097-1107.

Virgin, J. B., Metzger, J., and Smith, G. R. 1995. Active and inactive transplacement of the M26 recombination hotspot in Schizosaccharomyces pombe. Genetics 141:33-48.

Walker, P.D., Capadilupo, J., Wolf, W., and Carlock, L. 1996. Preprotachykinin and preproenkephalin mRNA expression within striatal subregions in response to altered serotonin transmission. Brain Res. 732:25-35.

White, B.C., Grossman, L.I., O'Neil, B.J., DeGracia, D.J., Newmar, R.W., Rafols, J.A., and Krause, G.S. 1996. Invited article: Global brain ischemia and reperfusion. Ann. Emerg. Med. 27:588-594.

Yang, M., Hayashi, K., Hayashi, M., Fujii, J.T., and Kurkinen, M. 1996. Cloning and developmental expression of a membrane type-matrix metalloproteinase from chicken. J. Biol. Chem. 271:25548-25554.

Yang, C., Tomkiel, J., Saitoh, H., and Earnshaw, W. C. 1997. Identification of an overlapping DNA-binding and centromere targeting domain of human CENP-C. Submitted to Mol. Biol. Cell.

Ye, S., Eriksson, P., Hamsten, A., Kurkinen, M., Humpries, S.E., and Henney, A.M. 1996. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J. Biol. Chem. 271:13055-13061.

Yeatman, T.J., Cher, M.L., Mao, W., Wlock, M., Tedesco, T. 1996. Identification of genetic alterations associated with the process of human experimental colon cancer liver metastasis in the nude mouse. Clin. Exper. Metastasis 14:246.


We thank A.S. Goustin, J. Kamholz, M. Shy, L. Gorssman, and H. Kuivaniemi for their contributions to this newsletter.


The CMMG News is edited by Anne E. Greb, M.S. (577-6298,
agreb@cmb.biosci.wayne.edu), and David D. Womble, Ph.D. (313-577-2374, dwomble@cmb.biosci.wayne.edu).

The online versions of the CMMG News and other information about the CMMG are available at the CMMG World Wide Web site: http://cmmg.biosci.wayne.edu


Center for Molecular Medicine and Genetics
Wayne State University School of Medicine
3216 Scott Hall
540 East Canfield
Detroit, MI 48201
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http://cmmg.biosci.wayne.edu