Blood, 15 March 2003, Vol. 101, No. 6, pp. 2077-2077
i to I and the eye
Asians with the adult i syndrome have cataracts; Europeans do
not. What can be the explanation?
Different cells have different metabolic needs; sometimes an enzyme
that functions admirably in one cell type might perform optimally in
another cell type if its properties were altered. In such instances
evolution has often avoided the "one size fits all" approach but
has instead tailor-made an enzyme for each tissue. Sometimes entirely
different genes are turned on in different tissues. For example, there
are 2 distinct pyruvate kinase genes: M for muscle
(also found in white blood cells) and L for liver (in
modified form, also in red cells). In other cases a more thrifty and
elegant mechanism has evolved, namely, differences in the transcription
and/or splicing of the same gene in different tissues. An extreme
example is the UDP-glucuronosyltransferase gene; this gene has no less
than 12 separate first exons. Thus, depending upon which promoter is
active, the N-terminal end of the transferase varies
and, with it, its properties such as substrate specificity. Gilbert
disease, well known to hematologists, is usually due to a polymorphism
of the promoter of the most 3' exon 1.
Predictably, such complexity in the steps leading to the formation of
an mRNA results in complexity of disease phenotypes ostensibly the
result of a deficiency of the same enzyme. Yu and colleagues (page
2081) have now solved the mystery of why Asian patients with the adult
i phenotype have congenital cataracts while this clinical feature is
not found in patients with other ethnic origins. They have discovered
that the i-branching
1-6-N-acetylglucosaminyltransferase that converts i to
I is one of those genes that offers each tissue a choice of
different exons, 3 to be exact. Yu et al found that when the mutation
was in the third exon, common to all 3 forms of the enzyme, cataracts
represented a part of the clinical picture. In contrast, when one of
the alternative first exons contains the mutation, only 1 of
the 3 transcripts was affected, and cataracts were not present.
The complex solutions that evolution has utilized to optimize the
functioning of cells have resulted in complexities of disease phenotypes that require considerable ingenuity to unravel.
Ernest Beutler
The Scripps Research
Institute
