Human Genetic Diseases 
Yuet Wai Kan, M.D., D.Sc. — Investigator 
Dr. Kan is also Louis K. Diamond Professor of Hematology in the Departments of Laboratory Medicine and 
Medicine at the University of California, San Francisco. He received his M.B., B.S. degree from the Univer- 
sity of Hong Kong Medical School and later the D.Sc. degree. After internship and residency at Queen Mary 
Hospital, Hong Kong, he received postdoctoral training in hematology at Peter Bent Brigham Hospital, 
the Massachusetts Institute of Technology, Royal Victoria Hospital at McGill University, and the Children's 
Hospital, Boston. Dr. Kan has received numerous honors, including the Gairdner Foundation Interna- 
tional Award of 1982. He is a fellow of the Royal Society ( London ) and a member of the National Academy 
of Sciences and the Academia Sinica (Taiwan ). 
THE focus of our research is the molecular 
basis of human genetic diseases affecting the 
hematopoietic cells. The two diseases we have 
studied in detail are sickle cell anemia and thalas- 
semia. Both are the results of abnormal globin 
production and constitute important health 
problems in the Mediterranean region, Africa, the 
Middle East, and Asia. In the United States these 
disorders occur frequently among people of Afri- 
can, Italian, Greek, and Asian descent. We are de- 
fining the mutations that give rise to these defects 
and devising DNA analysis for their detection. In 
addition, we are studying the factors that control 
the expression of globin genes in the red cell pre- 
cursors and the signals that switch from fetal to 
adult globin gene production. 
Previously we demonstrated that the common 
genetic defect in a-thalassemia is deletion of the 
a-globin structural gene. We also defined some of 
the molecular lesions in i8-thalassemia. These 
studies led to our ability to detect thalassemia by 
analysis of fetal DNA. 
We initiated a new method of linkage analysis 
using restriction endonucleases to detect poly- 
morphism in DNA sequences and applied it to 
tracing the evolution of the sickle and thalasse- 
mia mutations. Restriction enzyme site polymor- 
phism is now an important tool for detecting 
many genetic disorders and for mapping the ge- 
netic loci of many diseases. 
We developed a method for prenatal diagnosis 
of sickle cell anemia and thalassemia. Initially, 
fetal blood samples were required. With the ad- 
vent of recombinant DNA technology, mutations 
in the human genome can be analyzed directly 
using DNA obtained by amniocentesis or chori- 
onic villus biopsy, permitting early in utero diag- 
nosis of these conditions. 
Prenatal Diagnosis 
Currently we are refining the prenatal diagnos- 
tic tests to facilitate diagnosis of /3-thalassemia in 
those areas of the world where this disease is an 
important health problem. For these tests to be 
used routinely, simple and nonradioactive meth- 
ods are needed. The polymerase chain reaction 
(PGR), which amplifies specific segments of 
DNA many millionfold, has facilitated the design 
of rapid and nonradioactive tests for sickle cell 
anemia, a-thalassemia, and (8-thalassemia. 
Although prenatal diagnosis of sickle cell ane- 
mia and a-thalassemia is relatively simple be- 
cause the genetic defects responsible for them 
are known and are readily detectable, diagnosis 
of /3-thalassemia is more complex. Glose to 100 
different mutations have been found to cause the 
clinically important i8-thalassemia syndromes. It 
is necessary to determine which mutations pre- 
dominate in a particular region so the appro- 
priate DNA test can be chosen, and consequently 
we have defined the common mutations in geo- 
graphic areas where thalassemia is prevalent (Sar- 
dinia, other parts of Italy, Lebanon, and Ghina). 
With this knowledge, simple and nonradioactive 
tests are being devised to detect the various de- 
fects in these different areas. 
Control of Globin Gene Expression 
We are studying the factors that control the tis- 
sue- and development-specific expression of the 
human globin genes. Synthesis of these chains is 
precisely coordinated during development. The 
embryonic e- and f-globin chains, which are syn- 
thesized in the early embryo, are replaced in the 
fetus by the a- and 7-gIobin chains. Prior to birth, 
the 18-globin chain takes over from the 7-globin 
chain as the predominant globin chain. The fac- 
tors that control the expression of the ^-globin 
gene in the bone marrow cells and coordinate the 
developmental expression of the globin genes 
during development have not been elucidated. 
We are now studying the DNA sequences and pro- 
tein factors that govern the expression of these 
genes. 
We have defined some of the sequences neces- 
sary for the tissue-specific expression of the glo- 
bin genes. A DNA segment as short as 36 base 
pairs appears to enhance tissue-specific globin 
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