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 (page2081) 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.