Lübeck University. Germany: Evidence Found in Both Human Multiple Sclerosis Patients and
Experimental Mouse Models, According to Research Published in The
American Journal of Pathology
A new study published in The American Journal of Pathology
identifies a novel gene that controls nerve conduction velocity.
Investigators report that even minor reductions in conduction velocity
may aggravate disease in multiple sclerosis (MS) patients and in mice
bred for the MS-like condition experimental autoimmune encephalomyelitis
(EAE).
A strong tool for investigating the pathophysiology of a
complex disease is the identification of underlying genetic controls.
Multiple genes have been implicated as contributing to the risk of
developing MS. Unlike studies that have focused on genetic regulators of
inflammation, autoimmunity, demyelination, and neurodegeneration in MS,
this study focused on nerve conduction velocity. Investigators found
that polymorphisms of the inositol polyphosphate-4-phosphatase, type II
(Inpp4b) gene affect the speed of nerve conduction in both mice with EAE
and humans with MS.
“Impairment of nerve conduction is a common
feature in neurodegenerative and neuroinflammatory diseases such as MS.
Measurement of evoked potentials (whether visual, motor, or sensory) is
widely used for diagnosis and recently also as a prognostic marker for
MS,” says lead investigator Saleh M. Ibrahim, MD, PhD, of the Department
of Dermatology, Venereology, and Allergology of the University of
Lubeck (Germany).
Using several genomic approaches, the
investigators narrowed their search to the genetic region controlling
the enzyme inositol-polyphosphate-4-phosphatase II (INPP4B), the product
of which helps to regulate the phosphatidyl inositol signaling
pathway. Enzymes in this family are involved in cellular functions such
as cell growth, proliferation, differentiation, motility, survival, and
intracellular communication.
In one series of experiments, the
researchers analyzed the genetic locus EAE31, which previously had been
shown to control the latency of motor evoked potentials and clinical
onset of EAE in mice. Using advanced techniques including congenic
mapping,in silico haplotype analyses (computer simulations), and
comparative genomics (from rats, mice and humans), they were able to
“finemap” the focus to Inpp4b as the quantitative trait gene for EAE31.
When
the investigators analyzed this region in eight different strains of
mice, they found they could divide the strains into two groups based on
differences in amino acid sequences. The strains with the longer-latency
SJL/J allele had the two amino acids (arginine and proline), whereas
those with the shorter-latency C57BL/10S allele had others (serine and
histidine). “These data suggest that Inpp4b structural polymorphism is
associated with the speed of neuronal conduction,” comments Dr. Ibrahim.
In
another experiment, the scientists compared motor conduction velocity
in genetically modified mice with a mutant Inpp4b gene to that of
control mice. The nerve conduction in this group was slower than in the
control group.
Finally, the investigators studied INPP4B
polymorphisms in MS patients. They looked at two cohorts: one from Spain
(349 cases and 362 controls) and a second from Germany (562 cases and
3,314 controls). The association between the INPP4Bpolymorphisms and
susceptibility to MS was statistically significant when the cohorts were
pooled. However, although the Spanish cohort showed a strong
association between INPP4B and MS, the association was weaker in the
German cohort. “The exact reason for the diverging effect across these
populations remains unresolved,” states Dr. Ibrahim.
In an
accompanying commentary, Hans Lassmann, MD, of the Center for Brain
Research of the Medical University of Vienna (Austria) notes, “This
study represents an interesting example of how minor changes in
conduction velocity, which do not result in a clinical phenotype in
control populations, may aggravate disease in conditions such as EAE or
MS.” In other words, impaired nerve conduction may have a greater impact
on those with MS compared to healthy individuals. Noting that the study
reported no major loss of myelin in animals carrying the mutant allele,
Dr. Lassmann comments that it is still unclear which neurobiological
mechanisms underlie the INPP4B-associated impaired conduction. One
suggestion is that INPP4B may be involved in calcium ion signaling
within synapses, affecting neurotransmitter release.