It turns out that the aberrant function is in the synapse between the incoming nerve fibers of the nociceptor, the pain sensitive sensory apparatus in the peripheral organs and the signal-receiving spinal neurons (Figure). The missense mutation, even in a single allelic copy, results in the silencing of the secondary signal leading from the dorsal horn of the spine to the hypothalamus in the brain. From the phenotype point of view this may be thought of as a dominant negative mutation. There is an interesting lesson here with respect to a possible inability of complete gene inactivation to mimic the phenotypes sometimes caused by more subtle protein changes.
Sodium channels are wonderful pieces of protein machinery, with the major alpha polypeptide spanning nearly 2,000 amino acids. This traverses the lipid bilayer membrane 24 times, and has four pore-lining loops. That minor changes at strategic sequence positions of such proteins lead to significant changes of electrical properties is noteworthy. Even more so is the fact that another member of the same family, SCN9A, when mutated heterozygously, leads to a completely opposite effect, namely spontaneous pain attacks in paroxysmal extreme pain disorder.3
A second gene with enhanced GeneCards user views is SGK196 (Sugen Kinase 196) named after the biotech company that branded it as part of a quest for cancer-related protein kinases. This protein basically remained a functional “orphan” until the current publication of a paper in Science4 that identified it as catalyzing the phosphorylation of a glycosyl moiety on DAG1 (dystroglycan 1 or dystrophin-associated glycoprotein 1). In other words, what has been suspected for a long time (though with some doubts) to be a protein kinase, is in fact a glycosyl kinase. There are relatively few past examples of well-characterized kinases of this sort, as exemplified by the FAM20B enzyme, responsible for O-phosphorylation of xylose in extracellular matrix proteoglycans5. This discovery made it necessary to rename the gene from the nondescript SGK196 to the explicit protein O-mannose kinase (POMK), as it will soon appear in web databases.
Muscle integrity strongly depends on the successful interaction between laminin of the extracellular matrix and dystroglycan (DG) in the muscle sarcolemma. Healthy dystroglycan alpha chain (DAG1) undergoes a series of glycosylation steps, whose disruption leads to a variety of congenital muscular dystrophies, e.g., Duchenne muscular dystrophy (see MalaCards). There were genetic indications that an SGK196 mutation underlies muscular dystrophy,6 but the mechanism remained undeciphered. The current publication shows that the SGK196/POMK encoded protein catalyses the phosphorylation of mannose in the growing glycosyl moiety of dystroglycan. This then allows further maturation of the glycol moiety and affords normal function. Thus, deorphanization of SGK196 led to new insights on the molecular basis of a set of debilitating muscle diseases.
What characterizes both underscored studies is that their detailed molecular and cellular scrutiny provides new unexpected insight into how subtle protein changes lead to inherited diseases. Genetic web-based databases not only help attract attention to such interesting cases, but also serve as invaluable tools for comprehending the relevant, often convoluted molecular underpinnings.