Molecular genetics of inherited neuropathies

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Rinsho Shinkeigaku. 2006 Jan;46(1):1-18.

Molecular genetics of inherited neuropathies

(Original Full Text is in Japanese)

Takashima H.

Department of Neurology and Geriatrics, Kagoshima University Graduate

School of Medical and Dental Sciences.

Inherited neuropathies are clinically and genetically heterogeneous.

At least 28 genes and 12 loci have been associated with Charcot-Marie-

Tooth disease (CMT) and related inherited neuropathies. Most causes

of inherited neuropathy have been discovered by positional cloning

technique and in the past two years, the pace of CMT gene discovery

has accelerated. Genetic studies have revealed the following gene

mutations as the causes of inherited neuropathies; PMP22, MPZ, EGR2,

SOX10, SIMPLE/LITAF, ARHGEF10 for CMT1 (autosomal dominant

demyelinating form); GDAP1, MTMR2, SBF2/MTMR13, KIAA1985, NDRG1 PRX

for CMT4 (autosomal recessive demyelinating form), MFN2, KIF1B, RAB7,

GARS, NEFL, HSPB1, HSPB8 for CMT2 (autosomal dominant axonal form);

LMNA, GAN1, KCC3, TDP1, APTX, SETX for AR-CMT2 (autosomal recessive

axonal form); GIB1 for CMTX (X-linked CMT); DNM2 for CMT-DI

(autosomal dominant CMT with intermediate nerve conduction

velocities); and DHH for minifascicular neuropathy.

These discovered CMT causing genes/proteins include those which show

unpredictable correlations with the peripheral nervous system.

However, these genes/proteins are definitely important for the

peripheral nerve, and their discovery should pave the way for

dramatic progress in the understanding of peripheral nerve biology.

On the other hand, genotype-phenotype correlations of these genes are

also important in order to understand the pathomechanisms of

inherited neuropathy. Because, based on mutation studies, a large

number of genes associated with both the CMT1/4 and CMT2 forms have

been identified, it is usually difficult to predict the causative

gene based on clinical information from patients without specific

complications.

To clarify the specific features and molecular mechanisms of five

diseases that we previously reported, we reviewed recent progress in

HMSN-P linked to chromosome 3, CMT4F caused by PRX, CMT4A caused by

GDAP1, CMT4B2 caused by SBF2/MTMR13, and SCAN1 caused by TDP1. HMSN-P

is characterized by late onset, proximal dominant severe muscle

weakness, fasciculations, muscle cramp and sensory involvement. HMSN-

P is a primary neuronopathy. Mutations in periaxin are associated

with a broad spectrum of demyelinating neuropathies including DSS, a

sensory dominant form and early onset slowly progressive CMT.

Pathologically, loss of myelinated fibers, demyelination, small onion

bulb formations, tomacula formation and myelin foldings were seen in

sural nerves. Absence of septate like junction in the paranodal loop

suggests that periaxin could be required for the adhesion complex.

GDAP1 is a relatively common cause of CMT4. Half of reported patients

showed the demyelinating form, while the rest showed the axonal form.

The typical feature of CMT4A is paresis of the vocal cords and

diaphragm. CMT4B2 is characterized by autosomal recessive, juvenile

onset glaucoma and focally folded myelin in sural nerves. SBF2/MTMR13

mutations cause CMT4B2. Early onset glaucoma was seen in patients

with nonsense mutations. SBF2/MTMR13 and MTMR2, which is the cause of

CMT4B1, could be acting on the same 3-phosphoinositide signaling

pathway. Clinical phenotypes of patients with TDP1, APTX, or SETX

mutations share common clinical findings, namely cerebellar ataxia

and axonal neuropathy. TDP1 and aprataxin both act on the single

strand break repair pathway, with TDP1 working specifically on

topoisomerase I related SSBR.

Senataxin is a RNA helicase acting on RNA maturation and termination

in yeast. Since these three proteins share a common pathway,

disruption in any of them could induce a delay in the transcription

process. The low rate of protein supply could lead to deaths of large

neuronal cells.