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Charcot-Marie-Tooth Neuropathy Type 4C

Synonyms: CMT4C, Charcot-Marie-Tooth Disease Type 4C

, PhD, , MD, and , MD, PhD.

Author Information
, PhD
Department of Neurology - Charcot
National Center for Neurodegenerative Diseases
Centre Hospitalier Universitaire d'Angers
Angers, France
INSERM U679
Hôpital de la Pitié-Salpêtrière
Paris, France
, MD
Department of Neurology - Charcot
Centre Hospitalier Universitaire d'Angers
Angers, France
, MD, PhD
Département de Génétique et Cytogénétique
INSERM U679
Hôpital de la Pitié-Salpêtrière
Paris, France

Initial Posting: ; Last Revision: July 6, 2010.

Summary

Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is a demyelinating neuropathy characterized by early-onset severe spine deformities. The majority of affected children present with scoliosis or kyphoscoliosis between ages two and ten years, although earlier and later onset are observed. Slowly progressive neuropathy usually manifests in the first decade or adolescence, and occasionally earlier or later. Foot deformities (pes cavus, pes planus, or pes valgus) are common.

Diagnosis/testing.

Diagnosis is based on clinical findings, the results of motor nerve conduction velocity testing, and molecular genetic testing of SH3TC2 (KIAA1985), the only gene known to be associated with CMT4C. Because the diagnosis of CMT4C is defined by the presence of an SH3TC2 pathogenic variant, all individuals with CMT4C have a pathogenic variant in this gene.

Management.

Treatment of manifestations: Treatment of spinal deformities includes physiotherapy to preserve flexibility, bracing, and/or surgery, even at a young age. Treatment of foot deformities includes special shoes with good ankle support and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking, and in some cases surgery; associated pain and cramps may require medication.

Prevention of secondary complications: Daily heel cord stretching exercises and physical activity may help prevent contractures.

Surveillance: Monitor for onset and/or progression of scoliosis and changes in hand function and foot strength.

Agents/circumstances to avoid: Obesity; drugs and medications known to cause nerve damage (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin).

Other: Career and employment may be influenced by hand and/or foot weakness.

Genetic counseling.

CMT4C is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible if both pathogenic variants have been identified in the family.

Diagnosis

Clinical Diagnosis

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is characterized by the following:

  • Early and severe scoliosis, the presenting sign in most individuals [Kessali et al 1997, Gabreëls-Festen et al 1999, Azzedine et al 2006]
  • Neuropathy that usually develops in the first decade or adolescence, but occasionally manifests as delay in onset of independent ambulation in early childhood
  • Slowly progressive neuropathy; some individuals become wheelchair dependent because of involvement of the proximal lower limbs

Electrophysiology. The motor nerve conduction velocity (MNCV) of the median nerve is in the range observed in demyelinating disease: 4-37 m/sec, with a mean of 22 m/sec. MNCV is not correlated with disease duration.

Testing

Neuropathology. Nerve biopsies show a combination of morphologic features unique among the demyelinating forms of CMT [Kessali et al 1997, Gabreëls-Festen et al 1999, Gooding et al 2005], including the following:

  • Loss of myelinated fibers
  • Relatively few and small classic onion bulbs, as observed in CMT1A (see CMT1)
  • Basal membrane onion bulbs, consisting of concentric Schwann cell lamellae intermingled with single or double basal membranes or concentric basal membranes alone
  • Schwann cells of unmyelinated axons, often with very thin processes and connecting links between axons

Molecular Genetic Testing

Gene. SH3TC2 (KIAA1985) [Senderek et al 2003] is the only gene in which mutation is known to cause CMT4C.

Clinical testing

  • Sequence analysis. Because this disorder is defined by the presence of a pathogenic variant in SH3TC2, the mutation detection rate is 100%.
    Note: Because sequence analysis only detects sequence variants in the coding region of the gene, mutations such as exonic, multiexonic, and whole-gene deletions or gross genomic rearrangements would not be detected by this method.

Table 1.

Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4C

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SH3TC2 Sequence analysis 4Sequence variants 100%
1.

See Table A. Genes and Databases for chromosome locus and protein name.

2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a mutation that is present in the indicated gene

4.

Because sequence analysis only detects sequence variants in the coding region of the gene, mutations such as exonic, multiexonic, and whole-gene deletions or gross genomic rearrangements would not be detected by this method. For issues to consider in interpretation of sequence analysis results, click here.

Test characteristics. See Clinical Utility Gene Card [Aretz et al 2010] for information on test characteristics including sensitivity and specificity.

Testing Strategy

To establish the diagnosis in a proband, the following findings are necessary:

  • Clinical findings suggestive of CMT4C
  • Family history consistent with autosomal recessive inheritance (includes simplex cases, i.e., a single occurrence in a family)
  • MNCVs in the demyelinating range
    Note: In some cases, electroneuromyographic examination is incomplete or does not allow measurement of MNCVs because of the severity of the secondary axonal loss.
  • For simplex cases, exclusion of 17p11.2 duplication and of pathogenic variants in PMP22 (CMT1A) (see CMT1), MPZ (CMT1B) (see CMT1), and GJB1, which encodes connexin 32 (CMTX1) (see CMTX)
  • Molecular genetic testing of SH3TC2
  • If molecular genetic testing does not reveal two SH3TC2 pathogenic variants:
    • Another demyelinating neuropathy should be considered. Of note, two of ten (20%) individuals with various neuropathies associated with mutation of EGR2 had scoliosis [Szigeti et al 2007] (see also Differential Diagnosis);

      OR
    • A nerve biopsy may be needed to determine the nature of the neuropathy.
      Note: Nerve biopsy is of great diagnostic value in those with a demyelinating process.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is a demyelinating neuropathy characterized by early-onset severe scoliosis. Scoliosis as well as foot deformities were the presenting findings in most individuals with CMT4C.

Spine deformities (scoliosis or kyphoscoliosis) were observed between ages two and ten years in most cases [Kessali et al 1997, Gabreëls-Festen et al 1999], or more rarely, early in the second decade [Senderek et al 2003]. However, the disease may start at birth or much later: onset at age 37 years was reported in one individual [Colomer et al 2006].

Cumulative data indicate that scoliosis occurs in 72% of persons with CMT4C (Table 2). Scoliosis or kyphoscoliosis was found in:

In some cases the spine deformities are moderate; in others they are disabling. The curvature progressed three to five degrees annually and required surgery in 7% to 39% of reported cases (Table 2) [Kessali et al 1997, Gabreëls-Festen et al 1999].

Foot deformities (pes cavus, pes planus, or pes valgus) were reported in 72% to 100% of affected individuals [Senderek et al 2003, Azzedine et al 2006, Colomer et al 2006]. Foot deformities were first observed between ages two and ten years, were moderately or severely disabling, and required surgery in 6% (1/18) to 11% (3/28) of cases (Table 2).

Table 2.

Occurrence of Manifestations of CMT4C by Study

Study FindingStudy (Total Patients) Cumulative Data
Azzedine et al [2006] (28)Colomer et al [2006] (14)Senderek et al [2003] (18)
Age at Diagnosis 2-10 yrs4-39 yrsBirth-12 yrsBirth-39 yrs
Foot deformities Pes cavus 20/2814/14 18/1828/46
Pes planus 7/284/1811/46
Pes vagus 1/28--1/28
Total 28/2814/1413/18 255/60
Age at Onset 2-10 yrsNo data2-12 yrs2-12 yrs
Surgery 3/28None1/184/46
Spine deformities Total27/285/14 3 11/18 3 43/60
Age at Onset 2-10 yrs4 yrs4-12 4 yrs2-12 yrs
Surgery 5 + 6 6 = 13/281/14ND14/42
1.

Authors did not specify type of deformities.

2.

Authors did not specify the foot deformity in the one patient who had surgery.

3.

Authors did not indicate if they evaluated for kyphoscoliosis and/or lordosis.

4.

Onset of scoliosis was in infancy, age not reported.

5.
6.

Other. No data are available on cramps and pain in individuals with CMT4C. In general, cramps and pain are common in all forms of CMT, occurring in 80% of affected individuals, according to a recent study from the French CMT association [O Dubourg, personal communication]. Cramps are usually present from the onset, whereas pain may develop as the disease progresses.

Hypoacousis (slightly diminished auditory sensitivity) was reported in 7/46 persons with CMT4C [Senderek et al 2003, Azzedine et al 2006] and deafness (significant reduction of auditory sensitivity) in 7/46 persons [Senderek et al 2003, Colomer et al 2006]. The cumulative data from the literature showed that hypoacousis and deafness were each present in 15% of individuals (Table 3). For more detailed discussion of hearing loss in general, see Deafness and Hereditary Hearing Loss Overview.

Nystagmus was reported in 2/18 persons with CMT4C [Senderek et al 2003].

Pupillary light reflexes, facial paresis, hypoventilation/respiratory insufficiency, lingual fasciculation, head tremor, sensory ataxia, and diabetes mellitus were also reported (Table 3). The cumulative data from the literature showed that respiratory problems occurred in 20% of individuals with CMT4C. The other findings occur in 2% to 6% of individuals with CMT4C (Table 3).

Table 3.

Additional Clinical Findings in CMT4C by Study

Clinical FindingStudy (Total Patients)Cumulative Data
Azzedine et al [2006] (28)Colomer et al [2006] (14)Senderek et al [2003] (18)
Hypoacusis 5/28--2/187/46
Deafness --5/142/187/46
Nystagmus ----2/182/46
Pupillary light reflexes --3/14--3/46
Lingual fasciculation --3/14--3/46
Facial paresis 1/28----1/46
Head tremor --2/14--2/46
Sensory ataxia --2/14-->2/46 1
Respiratory insufficiency or hypoventilation 7/28 2 --2/189/46
Diabetes mellitus ----1/181/46
Romberg sign --2/14--2/46
1.

Gabreëls-Festen et al [1999] reported mild sensory ataxia in some individuals, without indicating the number of cases.

2.

Kessali et al [1997] reported that 7/11 persons required spine surgery because the severity of their deformities caused difficulty in sitting and pulmonary restriction.

Pregnancy. CMT appears to be an independent risk factor for complications during pregnancy and delivery.

  • The symptoms of CMT can worsen during pregnancy, in particular cramps, subjective sensitivity (e.g., paresthesias), difficulty walking, and fatigue.
  • Exceptionally, crises occurring during pregnancy do not subside post partum.
  • A retrospective study in Norway between 1967 and 2002 comparing 108 births to mothers with CMT with 2.1 million births to mothers without CMT determined that mothers with CMT more frequently needed interventions during delivery [Hoff et al 2005]. Bleeding post partum was also more common in mothers with CMT.
  • It has been postulated that fetal presentation tends to be abnormal because of the combination of CMT in the mother and fetus [Rayl et al 1996, Hoff et al 2005].

Genotype-Phenotype Correlations

Significant intrafamilial variability in the disease course makes it difficult to identify genotype-phenotype correlations [Kessali et al 1997, Gabreëls-Festen et al 1999, Senderek et al 2003, Azzedine et al 2005].

Prevalence

CMT4C (caused by mutation of SH3TC2) is a relatively frequent cause of the autosomal recessive demyelinating neuropathy CMT4. On the basis of the cumulative data presented in Table 4, the prevalence of CMT4C among those with CMT4 is approximately 17%.

Table 4.

Proportion of CMT4 Attributable to CMT4C by Study

StudyCumulative Data
Azzedine et al [2006] 1 Colomer et al [2006] Senderek et al [2003] 1
Individuals with CMT4C/all CMT4 10/38 (26%) 2
-- 4/14 3
6/55 4
2/21 5
12/90 total (13%)
22/128 (17%)
1.

Denominators represent the number of patients or families with CMT4 included in each study; numerators indicate the number with SH3TC2 pathogenic variants.

2.

Ten of 38 (26%) families with the CMT4 phenotype had SH3TC2 pathogenic variants [Azzedine et al 2005, Azzedine et al 2006].

3.

In 14 large and/or consanguineous families, five (36%) showed data consistent with but not significant for linkage to the CMT4C locus; however, SH3TC2 pathogenic variants were identified in only four of the five [Senderek et al 2003]. Note: In the family with suggestive linkage to CMT4C but no mutation of SH3TC2, linkage may have been fortuitous and/or the mutation may not have been detectable by sequence analysis.

4.

In 55 different families with CMT4, 15 showed data consistent with but not significant for linkage to CMT4C; only 6/15 (40%) had SH3TC2 mutations. Note: In the nine families with suggestive linkage to CMT4C but no mutation in SH3TC2, linkage may have been fortuitous or/and the pathogenic variants may not have been detectable by sequence analysis.

5.

In a group of 21 unrelated individuals with CMT4, two had pathogenic variants in SH3TC2.

Only one out of 19 (5%) Turkish families had an SH3TC2 pathogenic variant [Parman et al 2004].

Mutation of SH3TC2 has been found in individuals of diverse geographic origins (Algeria, Morocco, France, the Netherlands, Germany, Italy, Bosnia, Greece, Turkey, and Iran) and diverse ethnic origins (gypsies from Spain and Turkey) [LeGuern et al 1996, Gabreëls-Festen et al 1999, Guilbot et al 1999, Senderek et al 2003, Azzedine et al 2005, Azzedine et al 2006, Colomer et al 2006].

Differential Diagnosis

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) accounts for an estimated 10% of demyelinating CMT in simplex cases (i.e., a single occurrence in a family) in which the following have been excluded:

  • Duplication 17p11.2 that causes CMT1A (see CMT1)
  • Allelic variants in PMP22 that cause CMT1E (see CMT1)
  • Allelic variants in MPZ that cause CMT1B (see CMT1); and CMT2I and CMT2J (see CMT2)
  • Allelic variants in GJB1 (CX32) that cause CMTX1 (see CMTX1)

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4C (CMT4C), the following evaluations are recommended:

  • Examination by a child neurologist to evaluate for weakness and atrophy, gait stability, sensory loss, and other associated signs. It is important to distinguish between neuropathic pain and mechanical pain.
  • Examination by a pediatric orthopedist to assess the amount and progression of spinal curvature and to determine the extent of foot deformities
  • Examination by an otolaryngologist and/or ophthalmologist if problems with hearing or vision are present

Treatment of Manifestations

Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. See Grandis & Shy [2005] for a discussion of general treatment for CMT.

Treatment of spinal deformities

  • Physiotherapy helps to preserve flexibility.
  • If the curvature can be reduced with bracing, either a plaster or a thermo-molded plastic corset can be used.
  • If bracing and physiotherapy together are not sufficient to correct the scoliosis, surgery can be performed at an early age, even before the end of linear growth (Table 2) [Kessali et al 1997, Gabreëls-Festen et al 1999]. Surgical intervention requires consensus among the family, child (if possible), and attending physicians.

Treatment of foot deformities

Treatment of pain and cramps

  • Neuropathic pain can be treated with antiepileptic drugs (AEDs) (e.g., pregabalin, gabapentin).
  • Mechanical pain can generally be managed with a combination of physiotherapy and orthopedic treatment.
  • Cramps can be controlled with quinine.

Other

  • Some individuals require forearm crutches or canes for gait stability; some need wheelchairs.
  • Exercise to help the individual remain physically active according to his/her abilities is encouraged.

Prevention of Secondary Complications

Daily heel cord stretching exercises help prevent Achilles' tendon shortening.

Physical activity (e.g., swimming, bicycling, stretching) adapted to the abilities of each individual by a physiotherapist is useful to prevent contractures.

Individuals with diabetes mellitus need excellent foot care to avoid foot ulceration and necrosis.

Surveillance

Scoliosis needs to be closely followed. Monitoring four times a year is recommended.

Hand function and foot strength should be evaluated by an orthopedist every six months starting from the date of diagnosis.

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a range of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

See Grandis & Shy [2005].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Career and employment may be influenced by persistent weakness of hands and/or feet.

Anesthesia. Relatively few studies reported in the literature address risks of anesthesia in patients with CMT. No complications were observed after anesthesia in a large cohort followed in specialized consultation, but the advice of the anesthesiologist should be followed.

  • For general anesthesia, succinylcholine is usually contraindicated; however, it had no adverse effects in 41 persons with CMT [Antognini 1992].
  • Blockers of the neuromuscular junction should be used with caution.
  • Local-regional anesthesia, especially epidural analgesia at child birth, has been used without problems in CMT. This use of anesthesia should be discussed on a case-by-case basis with the anesthesiologist.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CMT4C are obligate heterozygotes (carriers) for an SH3TC2 pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the SH3TC2 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like CMT4C) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • NCBI Genes and Disease
  • TREAT-NMD
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 (0)191 241 8617
    Fax: 44 (0)191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Netherlands
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Charcot-Marie-Tooth Neuropathy Type 4C: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4C (View All in OMIM)

601596CHARCOT-MARIE-TOOTH DISEASE, TYPE 4C; CMT4C
608206SH3 DOMAIN AND TETRATRICOPEPTIDE REPEAT DOMAIN 2; SH3TC2

Gene structure. The normal gene comprises 17 coding exons spanning 62 kb of genomic sequence. For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, 20 pathogenic variants have been reported [Senderek et al 2003, Azzedine et al 2005, Azzedine et al 2006, Colomer et al 2006]. See Table 5.

Table 5.

Selected SH3TC2 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.28delG
(26delG)
p.Glu10SerfsTer4
(Arg9fs)
NM_024577​.3
NP_078853​.2
c.217_227delGCTGCTCGGAGinsCCAGTAAp.Ala73ProfsTer55
c.530-2A>G-- 2
c.920G>Ap.Trp307Ter
c.1178-1G>A-- 2
c.1586G>Ap.Arg529Gln
c.1747_1748delAGp.Arg583AlafsTer4
c.1969G>Ap.Glu657Lys
c.1972C>Tp.Arg658Cys
c.1982T>Cp.Leu662Pro
c.2191delGp.Glu731LysfsTer20
c.2491_2492delAGp.Leu832HisfsTer8
c.2642A>Tp.Asn881Ser
c.2710C>Tp.Arg904Ter
c.2829T>Gp.Tyr943Ter
c.2860C>Tp.Arg954Ter
c.3325C>Tp.Arg1109Ter
c.3326G>Cp.Arg1109Pro
c.3341delCp.Pro1114LeufsTer2
c.3601C>Tp.Gln1201Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

For frameshift mutations, 'Ter#' indicates the codon position in the new reading frame that ends in a stop (Ter). The position of the stop in the new reading frame is calculated starting at the first changed amino acid that is created by the frameshift (e.g., p.Glu10Ser) and ending at the first stop codon (Ter#), e.g., p.Glu10SerfsTer4). The shifted reading frame is thus open for '#-1' amino acids (thus in p.Glu10SerfsTer4, the new reading frame is open for three more codons, therefore terminating at codon 13).

1.

Variant designation that does not conform to current naming conventions

2.

Because the splice donor or splice acceptor site is changed, the change is expected to affect splicing (the nomenclature designation is r.spl?).

Normal gene product. The protein, known as the SH3 domain and tetratricopeptide repeats containing protein 2 (SH3TC2), comprises 1,287 amino acids. It contains two Src homology-3 (SH3) domains and ten tetratricopeptide repeat (TPR) domains.

Proteins with TPR domains are involved in many cellular processes through protein-protein interactions: in mitosis and RNA synthesis by their association in multiprotein complexes controlling cell-cycle or transcription machinery, in protein transport, and in chaperon functions [Blatch & Lassle 1999]. SH3 domains are highly conserved in eukaryotes, prokaryotes, and viruses, and mediate interactions with enzymes (tyrosine kinases, phospholipases cγ1 [PLCγ1] and PLCγ2, phosphoinositide 3-kinase and the NADPH-oxidase complex), cytoskeleton molecules (spectrin and nebulin), and myosins. They play important roles in cell-cell communication and signal transduction from the cell surface to the nucleus [Whisstock & Lesk 1999]. The spectrum of possible functions mediated by the TPR and SH3 domains is therefore large. The function of the molecule and the effect of the mutations will require further investigation in cellular and mouse models.

Abnormal gene product. Most mutation of SH3TC2 leads to loss or truncation of the protein, compatible with loss of function in an autosomal recessive disease. Thirteen of the 19 pathogenic variants described in the authors' series [Azzedine et al 2005, Azzedine et al 2006] and previously reported [Senderek et al 2003] directly or indirectly affected the structure or the number of TPR domains. For example, the p.Arg904Ter variant affected the TPR5 domain in exon 11 and reduced the number of TPR domains from ten to four. Furthermore, deletion of only the last TPR (TPR10) domain in the SH3TC2 protein caused by the p.Gln1201Ter variant reported by Senderek et al [2003] was sufficient to induce the phenotype.

References

Literature Cited

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Chapter Notes

Acknowledgments

We would like to thank Dr Merle Ruberg for critical review of the manuscript and Drs M Tazir, A Gabreëls-Festen, M Lammens, N Birouk, and O Dubourg for referral of affected individuals. This work was supported by the Association Française contre les Myopathies (AFM); The National center for neurodegenerative diseases, Department of Neurology, Section Charcot, CHU Angers; the Assistance Publique des Hôpitaux de Paris (AP-HP); the Institut National de la Santé et de la Recherche Médicale (INSERM) and GIS-Maladies Rares. Hamid Azzedine and Eric LeGuern are members of the French GIS-maladies rares research network on autosomal recessive forms of CMT.

Revision History

  • 6 July 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
  • 31 March 2008 (me) Review posted to live Web site
  • 10 February 2006 (ha) Original submission
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