New genetic cause of a form of inherited neuropathy
Discovery in siblings may hold answers to new gene therapies for Charcot- Marie-Tooth disease

Date:
August 3, 2020
Source:
University of Pennsylvania School of Medicine
Summary:
Inherited mutations in a gene that keeps nerve cells intact was
shown, for the first time, to be a driver of a neuropathy known
as Charcot- Marie-Tooth disease. This finding presents a clearer
picture of the disease's genetic underpinnings that could inform
the development of gene therapies to correct it.



FULL STORY ========================================================================== Inherited mutations in a gene that keeps nerve cells intact was
shown, for the first time, to be a driver of a neuropathy known as Charcot-Marie-Tooth (CMT) disease. This finding is detailed in a study
led by researchers in the Perelman School of Medicine at the University
of Pennsylvania, which published in Neurology(R) Genetics, an official
journal of the American Academy of Neurology.


==========================================================================
The findings, thanks to siblings treated at Penn since the late 1980s,
present a clearer picture of the disease's genetic underpinnings that
could inform the development of gene therapies to correct it.

The mutations in the gene known as dystonin (DST) add to a growing list
of malfunctions found to cause their type of CMT, known as CMT2, which
is defined by the loss of the nerve fibers, or axons, in the peripheral
nerve cells. The researchers also showed that these mutations affect
two key protein isoforms, BPAG1-a2 and BPAG1-b2, that are involved in
nerve fiber function. Mutations in other isoforms of the same protein
were previously tied to a blistering skin disease.

Neuropathies are common, occurring in nearly half of all diabetic
patients, while hereditary neuropathies affect nearly one of out of
2,000 people. CMT is a debilitating neurodegenerative disorder that
usually strikes in the second or third decade of life, and leaves
patients with numbness and weakness in the hands and feet, among other neurological-related conditions.

There are more than 100 mutations found to be associated with CMT,
with likely many more out there. Past studies from Penn researchers
have identified some of these mutations by studying patients treated at
Penn Medicine.

"We are determined to fill in the blanks of this giant jigsaw
puzzle," said senior author Steven S. Scherer, MD, PhD, a professor
of Neurology. "This latest paper is but one of many examples of where breakthroughs have happened between patients and the doctors at Penn
and the support of different organizations and institutions to bring
it all together." The researchers applied whole exome sequencing to
analyze the more than 30 million base pairs of DNA that encode the 20,000 proteins in humans. By examining three siblings -- two affected and one unaffected -- the researchers were able to deduce the genetic basis of mutations that caused the two siblings to be affected.

Backed by a mouse model from past studies showing a role of dystonin
in neuropathies, the researchers identified two recessive mutations
on the DST gene, each received from a biological parent, as the
culprit. Together, the two mutations in the affected siblings disrupt the BPAG1-a2 and BPAG1-b2 isoforms, the researchers found, which weakened
their axonal health. The DST gene gives rise to proteins that regulate
the organization and stability of the microtubule network of sensory
neurons to allow for transport of different cellular material along the
nerve fibers.

"We have collaborated with this family for 30 years, and now we finally
have an answer," Scherer said, "and the answer was a new genetic cause
of neuropathy." The findings put the field steps closer to developing
new targeted therapeutics as well as CMT gene therapies designed to
replace missing genes or correct mutations driving the disease. Clinical
trials to investigate these latest mutations and others are not far off
in the future, the researchers believe, particularly at an institution
like Penn, which is home to the second largest clinic for CMT patients
in the country and well-known for its gene therapy program.

"We are in the era where treatments for genetic diseases are possible,"
Scherer said. "This brother and sister stand to benefit from that approach because we know the gene that is missing, and if we could replace it,
that should at least prevent their progression."

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. William W. Motley, Stephan Zu"chner, Steven
S. Scherer. Isoform-specific
loss of dystonin causes hereditary motor and sensory neuropathy.

Neurology Genetics, 2020; 6 (5): e496 DOI:
10.1212/NXG.0000000000000496 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200803120159.htm

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