molecular pathology of Down syndrome to be elu- 
cidated. In other studies this laboratory has exam- 
ined the determination of laterality, a fundamental 
event in embryogenesis. They have mapped a muta- 
tion that results in random determination of situs 
(position for the heart and other internal organs) 
to murine chromosome 21. 
Methylmalonic acidemia (MMA) is an often fatal 
inborn error of metabolism that may arise from a 
deficiency of the enzyme methymalonyl CoA mu- 
tase (MCM). Cloning of the cDNA for MCM by the 
laboratory of Assistant Investigator Fred D. Ledley, 
M.D. (Baylor College of Medicine) has enabled 
characterization of the normal structure of the 
MCM enzyme and gene locus, classification of al- 
leles underlying MCM deficiency, and identification 
of mutations in cells from patients with MMA. 
Mouse MCM has been cloned and characterized 
and is homologous to the human enzyme in struc- 
ture and function. The present studies are directed 
toward elucidating the structure and function of 
MCM, the effect of mutations on enzyme activity, 
and the mechanisms by which MCM deficiency 
gives rise to a pathological phenotype. 
An abnormality of chromosome 15 causes two 
different genetic diseases, Prader-Willi syndrome 
and Angelman syndrome. These genetic disorders 
have been found to be determined by the sex of the 
parent that transmits chromosome 15. The labora- 
tory of the late Investigator Samuel A. Latt, M.D., 
Ph.D. (Children's Hospital, Boston) continues to 
investigate these disorders. The absence of the 
mother's chromosome 15 genetic material results 
in the Angelman syndrome, which is characterized 
by puppet-like movements and severe mental retar- 
dation, whereas absence of the father's chromo- 
some 15 genetic material causes Prader-Willi syn- 
drome, which is characterized by obesity and mild 
mental retardation. Further molecular studies of 
the abnormalities of the 15qllql3 subregion re- 
sponsible for these syndromes and the phenome- 
non of genetic imprinting are under way. 
Associate Investigator Robert L. Nussbaum, M.D. 
(University of Pennsylvania) and his colleagues 
study human heritable disease of unknown cause 
whose approximate genetic location is known from 
genetic mapping techniques. Examination of men- 
tal retardation with Xq27-28 fragile site (the fragile 
X syndrome) has demonstrated that the fragile site 
occurs at a region normally present in humans but 
one that undergoes an undefined alteration to pro- 
duce the various mutations that can occur in fami- 
lies. Efforts are under way to isolate the region con- 
taining the fragile site in order to understand the 
molecular basis for the disorder. The laboratory 
also has localized the disease gene of the hereditary 
retinal disease choroideremia and has obtained 
DNA sequences very near the relevant gene that are 
now being examined for portions of the 
choroideremia gene. The laboratory has provided 
the first regional localization of the disease gene for 
Lowe syndrome by genetic linkage and has devel- 
oped tightly linked, flanking markers for the disease 
locus. Work is in progress to isolate the gene re- 
sponsible for the disease by isolating DNA from a 
chromosome translocation in which the breakpoint 
of the translocation marks the position of the Lowe 
syndrome gene. 
The research activities of the laboratory of In- 
vestigator Stuart H. Orkin, M.D. (Children's Hospi- 
tal, Boston) center on the molecular biology and 
genetics of blood cells and the basis of inherited 
disorders in which the function of these cells is 
altered. The mechanisms controlling gene expres- 
sion in developing red blood cell precursors and 
the regulation and cellular biology of a system in 
white blood cells that produces bactericidal prod- 
ucts are under study. In the past year the gene 
has been cloned for a major transcription regula- 
tory protein for erythroid cells. This protein is be- 
lieved to play a major role in controlling the ex- 
pression of both globin and nonglobin genes in 
these cells. In addition, mutations have been de- 
fined in a novel white cell-specific cytochrome that 
lead to chronic granulomatous disease, an X-linked 
immune deficiency state in which microbes cannot 
be killed. The partial correction of this clinical dis- 
order in some patients by the administration of a 
cytokine (interferon-7) has led to a new approach 
to therapy. 
Work in the laboratory of Assistant Investigator 
David A. Williams, M.D. (Children's Hospital, Bos- 
ton) is directed at understanding blood cell forma- 
tion and developing approaches to the treatment of 
human diseases affecting blood cells. Blood cells 
are derived from stem cells, primitive progenitor 
cells that reside in the bone marrow, and some 
human diseases are caused by the lack of specific 
proteins in these cells. This laboratory is studying 
the use of modified viruses to deliver functioning 
genes into bone marrow stem cells to provide these 
proteins and correct the deficiency. 
The laboratory of Investigator Yuet Wai Kan, M.D. 
(University of California at San Francisco) continues 
to study genetic disorders of the red blood cell. 
Simpler and faster methods for prenatal diagnosis 
Continued 
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