Molecular Basis of Genetic Diseases 
and Chromosome Mapping 
Uta Francke, M.D. — Investigator 
Dr. Francke is also Professor of Genetics and Pediatrics at Stanford University School of Medicine. She 
received her M.D. degree from the University of Munich, Germany, trained in pediatrics at Los Angeles 
Children 's Hospital, and carried out postdoctoral research and clinical training in medical genetics 
at the University of California (Los Angeles and San Diego). Before moving to Stanford, Dr. Francke 
was Professor of Human Genetics and Pediatrics at Yale University School of Medicine. 
THE genetic maps of humans and the mouse 
are undergoing rapid growth and develop- 
ment. Through the efforts of many laboratories, 
including ours, several hundred homologous 
genes have been mapped in both species, and 
over 60 chromosome regions have been delin- 
eated that contain conserved groups of genes. 
Thus it has become possible, after mapping a 
gene in one species, to predict the location of its 
homologue in the other. Comparative mapping 
information is used to evaluate the possibility of a 
mouse mutation being a true model of a human 
genetic disorder. 
Our laboratory is employing in situ hybridiza- 
tion, with multicolor nonradioactive detection of 
chromosomal signals, as well as somatic cell ge- 
netic approaches, to locate cloned genes of 
known function on human and mouse chromo- 
somes. We are using this information to define 
candidate genes for human inherited disorders or 
for phenotypic mutations in mice and to further 
delineate regions that contain homologous genes 
in both species. Our goal is to identify genes in- 
volved in producing phenotypic abnormalities 
in chromosomal imbalance syndromes and in in- 
herited disorders, to understand their function, 
and to devise precise diagnostic tests and rational 
treatment strategies. 
Search for Genes Involved in Diseases 
In collaboration with the laboratory of Eric 
Shooter, Stanford University, we have mapped a 
peripheral myelin protein gene, identified by 
others as having a growth arrest function, to 
mouse chromosome 1 1 and human chromosome 
17. It thus became a candidate gene for involve- 
ment in the mouse mutation Trembler and the 
inherited human neuropathy Charcot-Marie- 
Tooth disease, type lA. Point mutations in this 
gene were indeed demonstrated in Trembler 
mice, and the work on the human disorder is in 
progress. 
In collaboration with Stuart Lefif and Tim Don- 
Ion, also at Stanford, we have assigned a gene 
whose product is involved in mRNA-processing 
(splicing) events to the region of human chromo- 
some 15 that is commonly deleted in patients 
with the Prader-Willi syndrome. In this deletion 
syndrome, hypotonia, hypogonadism, mental re- 
tardation, and obesity due to lack of appetite con- 
trol are associated with often submicroscopic 
(micro-) deletions of region 15qll.2-ql3. Since 
no gene of known function has yet been mapped 
to the smallest deletion overlap region, our as- 
signment of a gene to this region makes it a candi- 
date for contributing to the microdeletion pheno- 
type. It is well established that in Prader-Willi 
syndrome the chromosome with the deletion is 
paternally derived, while the maternally derived 
homologous genes do not appear to be expressed 
(imprinting) . If we can show that our candidate 
gene is also imprinted on the maternally derived 
chromosome, it would support the hypothesis 
that this gene contributes to the deletion 
phenotype. 
While the classical forms of X-linked-recessive 
progressive muscular dystrophy (Duchenne and 
Becker types) are due to deletions or mutations in 
the dystrophin gene on Xp21, there is a distinct 
autosomal recessive form of muscular dystrophy, 
affecting both sexes and clinically resembling 
Duchenne muscular dystrophy, for which the de- 
fect is unknown. We have collected and studied 
several families with more than one affected indi- 
vidual. The dystrophin-like gene on chromosome 
6 has been excluded as a candidate, and linkage 
to other chromosomal sites is being tested. We 
are also collaborating with Kevin Campbell 
(HHMI, University of Iowa, Iowa City), whose 
laboratory has characterized and isolated a dys- 
trophin-associated complex of glycoproteins lo- 
cated at the sarcolemma that interacts with dys- 
trophin. We have begun to map genes for these 
proteins to chromosomal sites as a prerequisite 
for testing them as possible candidates for in- 
volvement in autosomal childhood-onset progres- 
sive muscular dystrophy. 
Search for Mutations in Candidate Genes 
In order to find mutations in a candidate gene, 
we are employing screening methods in which 
the gene is amplified in small portions of DNA of 
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