Human Molecular Genetics and Comparative 
Gene 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 physical and genetic maps of the human 
and mouse have undergone spectacular 
growth and development in recent years. Almost 
500 homologous loci have been mapped in both 
species, and nearly 60 chromosome regions have 
been delineated that contain conserved syntenic 
groups of genes, through the efforts of many labo- 
ratories, including ours. Thus it has become possi- 
ble, after mapping a gene in one species, to pre- 
dict the location of the homologue in the other 
species. Comparative mapping information is 
also used to evaluate the possibility of a mouse 
mutation being a true model of a human genetic 
disorder. 
Our laboratory is employing chromosomal in 
situ hybridization and somatic cell genetic ap- 
proaches to locate cloned genes of know^n func- 
tion on human and mouse chromosomes. We are 
using this information to define candidate genes 
for human inherited disorders or for phenotypic 
mutations in mice and to delineate regions that 
contain homologous genes in both species. Our 
goal is to identify genes involved in producing 
phenotypic abnormalities in chromosomal imbal- 
ance syndromes and in inherited disorders, to un- 
derstand their function, and — based on this 
knowledge — to devise precise diagnostic tests 
and rational treatment strategies. 
Rett Syndrome 
Rett syndrome is a neurodegenerative disorder 
that affects 1 in 15,000 girls. The affected girl is 
usually the only affected person in her family. 
Although she appears normal at birth and in her 
early infancy, her development slows and re- 
gresses in early childhood. The disorder is char- 
acterized by stereotypic hand movements, loss of 
speech, and profound mental retardation with 
seizures and microcephaly. 
Although the progression of this disorder has 
been clinically delineated, the diagnosis remains 
tentative in the first few years. Pathophysiologi- 
cal and biochemical investigations have been 
unrevealing. The clinical picture is most consis- 
tent with progressive neuronal loss during early 
childhood, reaching a stable state that continues 
into adulthood. A genetic basis for this disorder 
has been established by concordance in identical 
twins and discordance in fraternal twins. A new 
mutation in a neuron-specific cis-acting gene on 
the X chromosome, which would be lethal in a 
male but allows females to survive due to their X 
chromosome inactivation mosaicism, appears to 
be the most plausible (although not the only pos- 
sible) explanation of the underlying defect. 
We are defining possible locations of the re- 
sponsible gene by identifying the regions of the 
maternal X chromosome shared by affected half- 
sisters who have a common mother. To find can- 
didate genes, we are carrying out chromosomal 
mapping studies of neuron-specific genes as they 
are cloned and become available. Genes that map 
to the X chromosome in a region not yet ex- 
cluded from containing the Rett syndrome locus 
(such as genes encoding synapsin I, synaptophy- 
sin, and serotonin receptor Ic) are being tested in 
25 unrelated Rett families for structural rear- 
rangements and sequence changes. Establishing 
the molecular defect in Rett syndrome will pro- 
vide not only a much needed diagnostic test but 
also information about the role of the specific 
gene in the development and function of the hu- 
man nervous system. 
Inherited Dwarfism 
Individuals with an autosomal recessive form 
of growth failure, despite having high levels of 
circulating growth hormone, are diagnosed as suf- 
fering from Laron dwarfism (LD) when they lack 
the activity of a specific growth hormone-bind- 
ing protein in serum. They are also characterized 
by low levels of insulin-like growth factors that 
are normally produced by liver cells in response 
to growth hormone. Therefore the underlying de- 
fect in LD is thought to involve the grov^h hor- 
mone receptor (GHR) . This receptor is encoded 
by a single gene, previously mapped by us to the 
proximal short arm of human chromosome 5 and 
to mouse chromosome 15. The sequence of the 
growT:h hormone-binding protein is identical to 
that of the extracellular domain of the GHR. Rear- 
rangements of the GHR gene have been observed 
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