Researchers
with the Ohio State University Comprehensive Cancer Center—Arthur G.
James Cancer Hospital and Richard J. Solove Research Institute led the
study and estimate that the mutation arose in the Middle East some
13,600 years ago. Only a mutation seen in cystic fibrosis that arose
between 11,000 and 52,000 years ago is believed to be older.
The
investigators described the mutation in people of Arabic, Turkish and
Jewish ancestry. It causes a rare, inherited vitamin B12 deficiency
called Imerslund-Gräsbeck Syndrome (IGS).
The
researchers say that although the mutation is found in vastly different
ethnic populations, it originated in a single, prehistoric individual
and was passed down to that individual’s descendents. This is unusual
because such “founder mutations” usually are restricted to specific
ethnic groups or relatively isolated populations.
The findings were published recently in the Orphanet Journal of Rare Diseases.
“Diagnosing
IGS is often time-consuming and inconclusive mainly because vitamin B12
deficiencies have many causes, so identifying this condition usually
involves excluding other possibilities,” says principal investigator
Stephan M. Tanner, research assistant professor of molecular virology,
immunology and medical genetics.
“Our
findings permit reliable genetic diagnostics in suspected cases of IGS
in that this mutation should be considered first when genetically
screening patients from these populations.”
Even
in rare disorders, founder mutations can cause a significant fraction
of all cases, he says. This mutation accounts for more than half of the
cases in these populations and for about 15 percent of cases worldwide.
“It is also often seen in expatriates living abroad,” Tanner says.
IGS
was identified just over 50 years ago. It occurs in children born with
two mutated copies of either the amnionless (AMN) or the cubilin (CUBN)
gene. When a genetic mistake is present in both copies of either of
these two genes, a person cannot absorb vitamin B12 in the small
intestine, resulting in the deficiency.
Children
with IGS experience a high risk of infections, fatigue, attention
deficit, paralysis and, ultimately, a form of anemia that can be fatal
if left untreated. An estimated 400 to 500 cases of IGS have been
described worldwide thus far. The incidence rate remains unknown. The
syndrome is treatable with life-long injections of vitamin B12.
For
this study, the researchers examined a total of 20 patients, 24
parents, 8 unaffected siblings, and 4 grandparents from 16 IGS families.
Because the researchers found the mutation in such diverse populations,
they were unsure whether it was a true founder mutation that first
arose in one individual and was passed down through many generations, or
whether it was simply a mutation that recurred frequently over time in
different populations.
Careful
analysis of the gene sequences on either side of the mutation (i.e.,
the haplotype in both the Muslim and Jewish families), however, pointed
to a single mutational event rather than repeated events.
