January 1, 1970 (Vol. , No. )
Doron Lancet Weizmann Institute of Science
Yaron Golan LifeMap Sciences
Gil Stelzer Weizmann Institute of Science
Find out which novel mechanisms of congenital diseases have been unearthed.
GeneCards, the gene compendium, automatically mines data from 110 sources, portraying a web card for every human gene. It allows users to perform advanced integrated searches that leverage this information. GeneCards also allows us to perform gene popularity trends, showing which genes have become desirable search targets. Two of the genes with steep popularity enhancements in September 2013 are discussed here.
The first up-and-coming gene, showing a 14-fold increase in GeneCards visits, is SCN11A, (sodium channel, voltage-gated, type XI, alpha subunit). A paper published this month in Nature Genetics1 describes a heterozygous missense mutation in this gene, leading to a complete loss of pain sensation in two patients. The tragic results of the inability to experience pain since birth are inadvertent self-mutilations, slow-healing wounds, and multiple painless bone fractures.
The SCN11A gene encodes a polypeptide component of a sodium-specific cation channel, one of a large family with nearly 20 members. The gene does not show clear differential expression signals in adult nervous tissues (e.g., BioGPS) but has a clear spinal signature in embryonic tissues (see LifeMap Discovery).
This is not the first time that sodium channels appear in the context of pain: Pain-related pathways (as gleaned via integration from 11 web sources in GeneCards) typically have a strong representation within this gene family. What is unusual and worthy of attention is the convoluted way in which the mutation gives rise to congenital analgesia. Of note, mouse knockout of the gene (colloquially named NaV1.9) results in no obvious basal phenotype, although it affects spontaneous pain behavior after peripheral inflammation.2 Yet, a seemingly innocent change of a single amino acid (Leu811Pro) abolishes pain.
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.
1 Leipold, E., et al., A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet, 2013. doi: 10.1038/ng.2767
2 Priest BT et al., Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci U S A, 2005, 102(26):9382–7.
3 Fertleman CR et al., SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron, 2006, 52(5):767–74.
4 Yoshida-Moriguchi, T., et al., SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Science, 2013. 341(6148): p. 896–9.
5 Koike, T., et al., FAM20B is a kinase that phosphorylates xylose in the glycosaminoglycan-protein linkage region. Biochem J, 2009. 421(2): p. 157–62.
6 Jae, L.T., et al., Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science, 2013. 340(6131): p. 479–83.