HUMAN MOLECULAR GENETICS AND GENE MAPPING 
Uta Francke, M.D., Investigator 
Research in Dr. Francke's laboratory has focused 
on mapping of genes to chromosomal sites and on 
molecular genetic studies of muscular dystrophy. 
L Comparative Mapping of Human and Mouse 
Chromosomes. 
Dr. Francke's laboratory has contributed to the 
gene map of humans and mice by mapping a num- 
ber of genes of known function to their chromo- 
somal sites in both species. The goal of this re- 
search is a detailed knowledge of the evolutionary 
relationships between human and mouse chromo- 
somes. With this information, hypotheses can be 
derived regarding candidate genes involved in 
human genetic disorders and in mouse mutations 
that have been described only on the phenotypic 
level. 
The possibility was tested that the gene for ad- 
ipsin, a regulatory protein that is produced in fat 
cells, could be involved in the genetic forms of obe- 
sity in mice {ob on chromosome 6 and db on chro- 
mosome 4). Although adipsin expression is greatly 
reduced in homozygous ob or db mice, the mouse 
adipsin locus was found to be on chromosome 10; 
thus it cannot be the site of the mutation in the ge- 
netically determined forms of obesity. 
Inhibin (INH) is a gonadal glycoprotein hormone 
that regulates secretion of pituitary follicle-stimulat- 
ing hormone (FSH). Two forms of inhibin that 
strongly inhibit FSH secretion share the same 
a-subunit, covalently linked to one of two distinct 
P-subunits ((3^ or p^). However, dimers of two 
p-subunits are potent stimulators of FSH synthesis 
and release. With cDNA probes (obtained from Dr. 
Anthony Mason), all three inhibin subunit genes 
have been mapped on human and mouse chromo- 
somes by Southern blot analysis of somatic cell hy- 
brid DNA and by in situ chromosomal hybridiza- 
tion. INHa and INHPg genes were assigned to 
human chromosome 2, regions q33-^qter and 
cen-»ql3, respectively, and to mouse chromosome 
1. The INH (3^ locus was mapped to human chromo- 
some 7pl5-*pl4 and mouse chromosome 13. The 
region of mouse chromosome 1 that carries other 
genes known to have homologues on human chro- 
mosome Iq includes the locus for juvenile sperma- 
togonial depletion (jsd). An inhibin gene could be 
involved in the jsd mutation, since adult homozy- 
gous male mice have elevated levels of serum FSH 
and their testes are devoid of spermatogonial cells. 
When the INHa and INHp genes in jsd mice were 
examined by Southern blot analysis, no evidence 
for major deletions or rearrangements was de- 
tected. The possibility that a point mutation in an 
inhibin gene is responsible for the jsd phenotype is 
being investigated. 
Receptor genes mapped in previous years in the 
human have now been assigned to mouse chromo- 
somes, in all cases to regions of known conserved 
synteny. The insulin-like growth factor I receptor 
gene is on mouse chromosome 7 concordant with 
the c-Fes proto-oncogene. In the human both loci 
are very close to each other, on the distal long arm 
of chromosome 15. Two receptor genes that are 
close to each other on human 5q were found to be 
syntenic on mouse chromosome 18. These are the 
genes for the ^^"^drenergic receptor and the plate- 
let-derived growth factor (PDGF) receptor. The 
glucocorticoid receptor gene {GRL) had previously 
been assigned to human chromosome 5 and mouse 
chromosome 18 by Dr. Francke and her colleagues. 
Regional mapping data reported by others had 
placed GRL on the proximal part of 5q, which is 
a region that contains loci homologous to genes 
on mouse chromosome 13, not 18. Therefore in 
situ hybridization studies were carried out with 
a human GRL probe. Results reassigned the GRL 
gene to 5q31-*5q32, consistent with expectations. 
This new location of GRL also suggests a potential 
relevance of its loss in 5q- deletions that are seen 
in hematopoietic disorders. 
II. Chromosomal Mapping of Human Genes Poten- 
tially Involved in Genetic Disorders. 
Efforts to map human genes to sites on human 
chromosomes have focused on 1) cloned genes 
known to be involved in genetic diseases; 2) genes 
specifically expressed in muscle or the nervous sys- 
tem that could potentially be involved in inherited 
disorders; and 3) genes involved in growth control, 
such as growth factors, their receptors, and other 
cell surface antigens or second messengers. The ra- 
tionale for the last is to see whether these genes 
could be colocalized with one of the 70 sites 
known on human chromosomes that show prefer- 
ential breakage in malignant cells. These studies 
were done in collaboration with the laboratories 
that had cloned the genes (see publications). 
Blast- 1 is a human activation-associated glycopro- 
tein expressed on the surface of leukocytes. The lo- 
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