by Long Le
Bloom syndrome is a rare autosomal recessive genetic disease that features
an elevated rate of sister chromatid exchange. There are less than 200 hundred
cases of bloom syndrome that have been reported. Bloom syndrome could be
underdiagnosed in some populations due to the differences in skin pigmentation
of various ethnic groups. Darker skins can give a person more protection
from various types of radiation. Small body size, sun- sensitive facial
skin lesions, immunodeficiency, and hypo- and hyperpigmented skin are just
some of the predominant clinical features of this syndrome (Ellis, 1995).
These features are the result of a deficiency of DNA repair enzymes. Examining
cells from a patient with BS shows genomic instability that includes vast
amounts of microscopic visible gaps, breakage and rearrangements. These
symptoms would usually indicate a defect in DNA repair or DNA metabolism.
As it turns out, several enzymes actively involved in DNA replication are
altered. These enzymes include DNA ligase I, uracil- DNA glycosylase, super-oxide
dismutase, topoisomerase II, and thymidylate synthetase (Weksberg, 1994).
This disorder is represented by a single gene defect. The defect in DNA
ligase I is due in-part to the ATP binding and hydrolytic activity of the
enzyme. Gene therapy to treat Bloom syndrome would be difficult because
it would raise ethical questions among people. Germ line gene therapy would
eliminate the disease. Some biologists would not even consider doing gene
therapy. Expression of Bloom syndrome is not an all or nothing event. Environmental
agents like UV light would affect people with light skin more than people
with darker skin due to the amount of melanin present. This syndrome is
most common in the Ashkenazi Jews (1 in 110). This is probably due to the
genetic isolation of their ancestral population. The frequency of the blm
allele in the Ashkenazi Jewish population was calculated to be .0091. This
is not in the Hardy Weinberg equilibrium because of the isolated population
that these people lived in at one time ( Ellis, 1994).
One major characteristic of Bloom syndrome is the elevated rate of sister
chromatid exchange. But there is a chance (1 in 5) that an affected person's
blood lymphocytes could have a normal SCE. A person like this is said to
have a high SCE/ low SCE mocaism. This mocaism usually occurs when a person
with this syndrome does not inherit the blm gene from a common ancestor.
These people are not homozygous for the mutation at blm gene, but instead
are compound heterozygous. Due to the hypermutability of Bloom syndrome,
low-SCE cell population can arise by some somatic mutational event. To test
this theory, somatic intragenic recombination was done. This technique involves
crossing over between the different mutated site in the paternally derived
and the maternally derived genes in a somatic stem cell. A functional wild
type blm that corrects the high SCE phenotype of BS cell resulted from this
procedure. A high rate of SCE in BS cells occurs if you inherit the blm
genes identical to your ancestor. This elevated sister chromatid exchange
may play a role in the high cancer risk of persons with Bloom syndrome.
Cancers caused by BS are the result of genomic instability. This instability
can cause protooncogene and tumor suppressor genes to become mutant and
can cause uncontrollable cell division leading to cancer ( Ellis, 1995).
The blm gene for Bloom syndrome was mapped to chromosome 15q26.1. By using
RFLPs from the DNA of affected children from consanguineous marriages, they
were able to map this gene. This method is call "homozygosity mapping"
by the authors. The protooncogene FES was found to be tightly linked to
the blm gene in 25 of 26 individuals with Bloom syndrome. These people came
from consanguineous families. Protooncogene FES is a polymorphic tetranucleotide
repeat in an intron. This could explain why BS is more common in Ashkenazi
Jews. The founder effect hypothesis can explain the increased frequency
of the blm gene in Ashkenazi Jews. The linkage between Fes gene and blm
gene only occur 33% of the time in the general population ( Ellis, 1994).
It has been proven that Bloom syndrome is a rare autosomal recessive disease,
which lacks in DNA repair enzymes resulting in genomic alterations. There
is an increase risk of cancer, particularly leukemia, in Bloom syndrome
patients. Elevated rate of sister chromatid exchange can be used to characterize
this disease. The blm gene was mapped on chromosome 15q26.1 by using RFLPs
from DNA of BS patients from consanguineous families. Protooncogene FES
was also found to be linked to the blm gene. BS individuals usually die
at a young age, but some have survive to their forties.
Ellis, A. Nathan. Somatic Intragenic Recombination. Phenotype of Bloom Syndrome
Cells. American Journal of Human Genetics 57:1019-1027, 1995.
Ellis, A. Nathan. Linkage Disequilibrium in Ashkenazi Jews with Bloom Syndrome.
American Journal of Human Genetics 57:453-460, 1994.
Weksberg, Rosanna. Low-Sister-Chromatid-Exchange of Human Tumor Development.
American Journal of Human Genetics 57:994-997, 1995.
Woodage, Trevor. Bloom Syndrome and Maternal Uniparental Disomy for Chromosome
15. American Journal of Human Genetics 55:74-80, 1994.
Return Case Studies in Virtual Genetics