November-December 2006, Volume 3, Issue 6
The Devil Is in the Details
Published on: November 01, 2006
Almeida AM, Murakami Y, Layton DM, et al. Hypomorphic promoter
mutation in PIGM causes inherited glycosylphosphatidylinositol
deficiency. Nat Med 2006;12:846-51.
Somatic cell mutation of the gene that encodes PIGA results in the
loss of formation of GPI-anchored proteins and is associated with PNH.
In this paper, the investigators describe an autosomal recessive
disease that results in GPI deficiency. In uncovering the etiology of
childhood thrombosis and seizures in two unrelated families (but each
consanguineous), a HAM test was found to be positive. GPI expression
was reduced in both patients in some but not all hematopoietic cells.
By homozygosity mapping and SNP analysis of the two families, they
closed in on the PIGM gene as the possible culprit. Cell lines were
isolated from the affected patients and their parents and radiolabeled
glycolipids were isolated and analyzed. The products reached the Gln
acyl PI stage (Figure), but the cell lines failed to add additional
mannose and PEtN residues — implicating either PIGM or PIGX as the
defective step. The combination of genetic information with the
biochemical findings pointed to PIGM as the mutated gene.
The analysis put forth by this group to explain the
clinical course of two families with children who presented with
thrombosis at a young age is not only an admirable piece of detective
work but also a lesson in the application of biochemical insight into
their genetic findings. Although it would be attractive to place the
defect that the investigators uncovered in the context of more general
clinical application, the thoroughness of their studies (which enabled
them to discern a cellular defect) is the major take-home lesson from
this work. The mutation is not in the expressed enzymatic portion of
the gene, but rather in the upstream promoter that binds the
transcription factor Sp-1. In explaining why a gene, PIGM, that is
important in development, may lead to only mild neurological defects,
acetylation status of the PIGM locus is suggested to play a role in
promoting sufficient biosynthesis of the PIGM product to overcome the
defect in Sp-1 binding. Alternatively, other promoters were detected
(e.g., GATA) that may induce expression in a more tissue-restricted
manner. Since these enzymatic pathways play a critical role in
development across a number of tissues, it is difficult to surmise
whether other defects will be uncovered to explain some similar
thrombotic complications or whether this enzymatic step is at the
threshold of sustaining development but still yields clinically
significant findings when affected.
Conflict of Interests
Dr. Petruzzelli indicated no relevant conflicts of interest.
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