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One Mutation, Two Diseases: Charcot-Marie Tooth Disease and Glomerular Disorder Linked By Membrane Dysfunction

Robinson, Richard

doi: 10.1097/01.NT.0000412337.93016.85
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Investigators report finding that a mutant INF2 (inverted formin-2) is responsible for both a form of Charcot-Marie-Tooth disease (CMT) and a kidney disorder, focal segmental glomerulosclerosis (FSGS), and the discovery provides insight into the biology of CMT.

Only a few letters separate “neurology” from “nephrology,” but there has always been a large gulf between the specialties themselves. A new discovery builds a small but significant bridge between the two, showing that a single gene is responsible for both a form of Charcot-Marie-Tooth disease (CMT) and a kidney disorder, focal segmental glomerulosclerosis (FSGS).

The gene, called INF2 (inverted formin-2), helps control actin dynamics, and its mutation appears to disrupt membranes in both peripheral nerves and the glomerulus of the kidney's nephrons. The discovery, which was described in the Dec. 22 New England Journal of Medicine, means “we've really got a new insight into the biology of CMT,” according to one expert.

The combined disorder first came to the attention of nephrologists in France, who were surprised to find several patients with both kidney failure and CMT.

“For a neurologist, if you have one patient among a hundred with renal failure, it is not very surprising, because many patients have renal failure,” said Benoît Funalot, MD, PhD, co-author and associate professor of neurology and genetics at the University of Limoges, France. “But from a nephrological point of view, when several patients with the same renal disorder develop CMT, this is something that draws their attention. It was much more clear for nephrologists than neurologists that the association was due to a single gene, and not to chance.” Those nephrologists, led by Corinne Antignac, MD, PhD, in Paris, contacted Dr. Funalot, who had his own CMT patient with a severe nephropathy.

A few cases of both CMT and FSGS had been described in the past, and INF2 was known to be responsible for about one in six cases of autosomal dominant FSGS without neuropathy. This led the investigators to wonder whether the gene might be responsible for both diseases in their patients.



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The investigators enrolled 16 index patients from 16 unrelated families. There are 40-plus genes known to cause CMT, with the large majority due to mutations in either peripheral myelin protein 22 (PMP22) or myelin protein zero (MPZ), so they first ruled out PMP22 and MPZ mutations in each patient. They then sequenced the INF2 gene.

Twelve of the 16 patients carried heterozygous mutations in the gene, all in exons 2 or 3, and all having an impact on a specific portion of the INF2 protein involved in binding to other proteins. In families with multiple affected members, the mutation segregated with the disease, and no INF2 mutations were found in 670 control chromosomes, or in 50 CMT patients with no known renal disease.

The median age at onset of peripheral neuropathy was 13 years, and ranged from age 12 to 47. Most patients had moderate to severe clinical symptoms at diagnosis, including impaired ambulation, reduction in hand function, muscle wasting, and loss of deep tendon reflexes. Median nerve conduction velocities were reduced, and the few available sural nerve biopsies indicated a marked decrease in myelinated fibers, consistent with a diagnosis of intermediate-type CMT. Onset of proteinuria was at a median age of 18 years (range 10 to 21 years), and 11 patients developed end-stage renal disease by age 21, requiring either dialysis or kidney transplant.

“In these patients the axonal loss occurs quite early. But is it a primary demyelinating disorder that quickly results in axonal loss, or do both problems occur together? We don't know,” said Dr. Funalot. In two patients who underwent brain MRI, imaging suggested an age-related white matter hyperintensity and ventricular dilation, but this, too, requires more investigation. And while their initial investigations suggest that INF2 mutations always lead to kidney disease, the sample size was relatively small, he said. “We still need to determine if this gene can be mutated in patients without such an overt kidney disorder.”

INF2 is known to be involved in remodeling of the actin and microtubule cytoskeletons, and promotes not only actin polymerization but also depolymerization and severing of filaments, Dr. Funalot explained. It carries out these functions through its interactions with other proteins, especially myelin and lymphocyte protein (MAL). MAL is a major component of myelin, and also occurs in podocytes, the cells within the glomerulus that help filter the blood through their elaborate membranous “feet.”

Disease-causing mutations occurred in the region of the protein most involved in interactions with other proteins, including MAL, and the mutations that caused both CMT and FSGS affected the interacting domain more severely than those known to cause FSGS alone. The investigators showed that CMT-causing mutations led to a mislocalization within the cell of both INF2 and MAL, as well as another INF2 partner called CDC42 (cell division cycle 42). This was accompanied by a reduction in the number of long actin fibers and disorganization of the microtubule network within Schwann cells in a mouse model. Because actin is involved in the formation of the myelin sheath, the overall effect, Dr. Funalot said, is likely that myelin formation and maintenance is disrupted by the mutations.

For the neurologist, Dr. Funalot said, the most immediate take-home message is that CMT patients without a known gene mutation may benefit from a simple screening test for proteinuria. A positive result could be followed by a gene test for INF2 mutation, which he said is relatively rapid and inexpensive, since the known culprit mutations are clustered in a small portion of the gene.

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James Lupski, MD, PhD, professor and vice chairman of molecular and human genetics, and professor of pediatrics at Baylor College of Medicine in Houston, agrees that screening such patients is a good idea. “We never really know until we get it out there in clinical practice” what the frequency of a new mutation will be, he said. “Even one percent is a significant number of cases, and you can better manage their care by virtue of anticipatory guidance regarding kidney disease.”



More broadly, he said, the new gene provides “new insight into the biology of CMT. I think it's actually a big deal — this is an important paper.”

The fact that CMT can be caused by so many different genes “indicates that anything that perturbs the function of the nerve, so that it can no longer propagate the signal, can lead to neuropathy, one that may take decades to manifest.”

“In both the neuropathy and the glomerular disorder, you are dealing with cells that have had to specialize, creating very unusual membrane structures. The Schwann cell wraps many times around the axon, while the podocyte must have a very large surface area to deal with filtration.” The remarkable thing, he said, “is that one protein is involved in solving this problem in both. This shows us we have a lot to learn here.”

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• Boyer O, Nevo F, Plaisier E, et al. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. New Engl J Med 2011;365:2377-2388.
    ©2012 American Academy of Neurology