Kessali et al. (1997) reported 2 large consanguineous Algerian families with autosomal recessive demyelinating CMT. Mean age at onset was 5.2 years (range 2 to 10 years). All patients had foot deformities and scoliosis, often requiring surgery. Motor ... Kessali et al. (1997) reported 2 large consanguineous Algerian families with autosomal recessive demyelinating CMT. Mean age at onset was 5.2 years (range 2 to 10 years). All patients had foot deformities and scoliosis, often requiring surgery. Motor nerve conduction velocities were severely decreased, and sural nerve biopsy of 1 patient showed concentric Schwann cell proliferation with multiple small onion bulbs. Linkage analysis excluded known CMT loci. Gabreels-Festen et al. (1999) reported the phenotypic findings in 5 Dutch families, a Turkish family, and a sporadic patient with a unique type of autosomal recessive demyelinating CMT. In addition to classic CMT features, such as distal muscle atrophy and weakness, areflexia, foot deformities, and distal sensory impairment, many patients had early onset of a severe scoliosis, often requiring surgery. Nerve biopsy findings were characterized by an increase of basal membranes around myelinated, demyelinated, and unmyelinated axons, relatively few onion bulbs, and, most typically, large cytoplasmic extensions of Schwann cells. Senderek et al. (2003) reported phenotypic and molecular characterization of 17 patients from 11 families, as well as 1 sporadic case, with autosomal recessive demyelinating CMT linked to chromosome 5. Age at onset ranged from infancy to 12 years, and many patients had a delay in learning to walk. Prominent scoliosis was observed in 11 patients. Mean median motor nerve conduction velocity (NCV) was 22.6 m/s, and nerve biopsy, when obtained, showed demyelination, onion bulb formation, and extended Schwann cell processes. Other classic CMT features included foot deformities, distal muscle weakness and atrophy, mild distal sensory loss, and decreased reflexes. Colomer et al. (2006) reported detailed clinical features of 15 individuals from European Gypsy families with CMT4C and homozygous for the R1109X mutation (608206.0006). Nine patients were members of a large consanguineous Spanish Gypsy kindred (Gooding et al., 2005), with 3 patients each from 3 branches of the family. Within each branch, affected individuals were sibs or first cousins, whereas the relation between branches was as first cousins once removed or second cousins. In the first branch, patients had a relatively late onset at ages 16, 26, and 37 years, respectively, with mild foot deformities, lower limb weakness and walking difficulties. One patient could walk with crutches, 1 could stand with support, and the youngest remained ambulatory. All 3 eventually developed mild upper limb involvement. All also had cranial nerve involvement with deafness, slow pupillary light reflexes, and lingual fasciculations. None had scoliosis. Three patients in the second branch of the family had a more severe disease with onset at ages 6, 6, and 7 years, foot deformities, and distal lower limb weakness and areflexia; 1 had severe scoliosis. There was no evidence of cranial nerve involvement. Affected members of the third branch of the family were the most severely affected. Two boys were hypotonic from birth, never achieved ambulation, had severe scoliosis, and remained wheelchair-bound and totally disabled with generalized muscle weakness and wasting. One died at age 22 years. An affected sister had delayed motor development and severe sensory ataxia, but no scoliosis. Two patients showed prolonged brainstem auditory evoked potentials (BAEP), but no other cranial nerve findings. Six additional patients with the R1109X mutation from 5 different families showed variable features, including 4 with delayed motor development, 3 with scoliosis, and 4 with abnormal BAEP recordings. Common features included foot deformities, distal muscle weakness and atrophy, and difficulty walking. Colomer et al. (2006) noted the highly variable phenotype associated with the same homozygous mutation, especially in the large Spanish Gypsy kindred, and suggested that genetic modifiers may play a role in the manifestation of CMT4C. Azzedine et al. (2006) reported 10 families with CMT4C from Europe and North Africa. Onset occurred between ages 2 and 10 years, and almost all patients presented with scoliosis, kyphoscoliosis, and foot deformities. The functional disability was low, and most patients could walk without help. Median motor nerve conduction velocities were decreased but not associated with disease duration. Azzedine et al. (2006) emphasized that spine deformities are a hallmark of this disorder.
In affected members of 11 families and a sporadic patient with CMT4C, Senderek et al. (2003) identified 11 different mutations in the SH3TC2 gene (see 608206.0001-608206.0005), of which 8 were protein-truncating and 3 missense. Segregation analyses were consistent ... In affected members of 11 families and a sporadic patient with CMT4C, Senderek et al. (2003) identified 11 different mutations in the SH3TC2 gene (see 608206.0001-608206.0005), of which 8 were protein-truncating and 3 missense. Segregation analyses were consistent with autosomal recessive inheritance. In 8 affected members of a large Spanish Gypsy kindred with CMT4C, Gooding et al. (2005) identified a homozygous mutation in the SH3CT2 gene (R1109X; 608206.0006). Four additional European Gypsy patients also had the mutation. Haplotype analysis indicated a founder effect. In affected members of 10 families with CMT4C, Azzedine et al. (2006) identified compound heterozygous or homozygous mutations in the SH3TC2 gene. The authors identified a total of 10 different mutations, including 8 novel ones. R954X (608206.0005) was a recurrent mutation, occurring in 4 Dutch families and 1 Algerian family. Some of the families had been reported by Kessali et al. (1997) and Gabreels-Festen et al. (1999). Lupski et al. (2010) reported 4 sibs with CMT4C caused by compound heterozygous mutations in the SH3CT2 gene: R954X (608206.0005) and Y169H (608206.0008). Three additional family members who were heterozygous for the R954X mutation, resulting in loss of function, had a mild mononeuropathy of the median nerve, and 2 additional family members heterozygous for the Y169H mutation had an apparently autosomal dominant axonal neuropathy with definite median nerve involvement, as shown by electrophysiologic studies. These findings suggested a toxic gain of function for the Y169H-mutant protein. Lupski et al. (2010) commented on the subtle autosomal dominant phenotypes segregating independently with the respective mutations.
Gooding et al. (2005) found that CMT4C occurs across European Gypsy populations, with prevalence among Spanish Gypsies. Other inherited conditions associated with peripheral neuropathy common in the European Gypsy population include HMSNL (601455), HMSNR (605285), and CCFDN (604168). ... Gooding et al. (2005) found that CMT4C occurs across European Gypsy populations, with prevalence among Spanish Gypsies. Other inherited conditions associated with peripheral neuropathy common in the European Gypsy population include HMSNL (601455), HMSNR (605285), and CCFDN (604168). Claramunt et al. (2007) found that 10 of 20 Spanish Gypsy families with autosomal recessive demyelinating neuropathy had CMT4C. The most common mutation was R1109X, which was identified in 20 of 21 mutation-carrying chromosomes. Haplotype analysis indicated a founder effect that likely arose about 225 years ago, probably as a result of a bottleneck. Among the cohort of 20 families, 4 had HMSNL, and 3 had HMSNR. In a French Canadian cluster of 17 CMT4C patients from Quebec, Canada, Gosselin et al. (2008) identified the R954X mutation in homozygosity in 12 patients from 7 families and in compound heterozygosity with an unidentified mutation in 2 patients from 1 family. In total, the R954X mutation was identified in 26 (76%) of 34 alleles from 10 families. Thirteen patients, including 10 homozygous for R954X, originated from a series of coastal villages in the Gaspesie, a sparsely populated peninsular region of Quebec, near the Maine/U.S. border. The villages are distributed along a 150-km stretch of the western shore of Chaleur Bay. Haplotype analysis demonstrated that at least 2 distinct CMT4C mutations are present in the French Canadian population and indicated a founder effect for the R954X mutation. Houlden et al. (2009) identified a homozygous R954X mutation in affected members of 4 English families with CMT4C. A fifth English family was compound heterozygous for R954X and E657K (608206.0007). There was significant phenotypic variability between these families: some presented with severe childhood onset, respiratory and cranial nerve involvement, and became wheelchair-bound, whereas others had only mild scoliosis and foot deformity. One patient homozygous for the R954X mutation had a superimposed inflammatory neuropathy associated with steroid treatment for ulcerative colitis. By screening of the SH3TC2 gene in 60 unrelated Czech patients with CMT, Lassuthova et al. (2011) found that 13 (21.7%) carried at least 1 pathogenic mutation and 7 (11.6%) had 2 pathogenic mutations. Nine novel mutations were identified. Screening for only the R954X mutation showed that 8 (1.94%) of 412 additional patients carried this variant; overall, R954X accounted for 63% of the mutant alleles. Lassuthova et al. (2011) concluded that CMT4C is relatively common in the Czech population.
Charcot-Marie-Tooth neuropathy type 4C (CMT4C) is characterized by the following:...
DiagnosisClinical DiagnosisCharcot-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. TestingNeuropathology. 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 TestingGene. 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 mutation in the causative gene, 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 4CView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySH3TC2 Sequence analysis Sequence variants 100% 2 Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo 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 mutations 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 mutations: Another demyelinating neuropathy should be considered. Of note, two of ten (20%) individuals with various neuropathies associated with mutations in EGR2 had scoliosis [Szigeti et al 2007] (see also Differential Diagnosis); ORA 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 disease-causing mutations 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 disease-causing mutations in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in SH3TC2.
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....
Natural HistoryCharcot-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:96% of affected individuals (27/28) in the largest series reported to date [Azzedine et al 2006]; 47% (11/18) of individuals studied by Senderek et al [2003]; 36% (5/14) of individuals studied by Colomer et al [2006]. 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 StudyView in own windowStudy FindingStudy (Total Patients) Cumulative DataAzzedine 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 yrsFoot deformities Pes cavus 20/2814/14 18/1828/46Pes planus 7/284/1811/46Pes vagus 1/28--1/28Total 28/2814/1413/18 255/60Age at Onset 2-10 yrsNo data2-12 yrs2-12 yrsSurgery 3/28None1/184/46Spine deformities Total27/285/14 3 11/18 3 43/60Age at Onset 2-10 yrs4 yrs4-12 4 yrs2-12 yrsSurgery 7 5 + 6 6 = 13/281/14ND14/421. 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. Kessali et al [1997] 6. Gabreëls-Festen et al [1999]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 StudyView in own windowClinical FindingStudy (Total Patients)Cumulative DataAzzedine et al [2006] (28)Colomer et al [2006] (14)Senderek et al [2003] (18)Hypoacusis 5/28--2/187/46Deafness --5/142/187/46Nystagmus ----2/182/46Pupillary light reflexes --3/14--3/46Lingual fasciculation --3/14--3/46Facial paresis 1/28----1/46Head tremor --2/14--2/46Sensory ataxia --2/14-->2/46 1 Respiratory insufficiency or hypoventilation 7/28 2 --2/189/46Diabetes mellitus ----1/181/46Romberg sign --2/14--2/461. 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].
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]....
Genotype-Phenotype CorrelationsSignificant 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].In 28 individuals with CMT4C, Azzedine et al [2006] showed the lack of correlation between the nature and the position of the mutation, disease duration, and the stage of disability. They also reported intrafamilial variability in age at onset, disease duration, and stage of disability. Colomer et al [2006] reported clinical variability in 14 affected individuals who had the same mutation.
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:...
Differential DiagnosisCharcot-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)Mutations in PMP22 that cause CMT1E (see CMT1) Mutations in MPZ that cause CMT1B (see CMT1); and CMT2I and CMT2J (see CMT2) Mutations in GJB1 (CX32) that cause CMTX1 (see CMTX1)
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4C (CMT4C), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsTreatment 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 Special shoes with good ankle support and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking Physiotherapy to preserve flexibility In approximately 9% of individuals, surgery to correct severe pes cavus deformity (Table 2) [Kessali et al 1997, Guyton & Mann 2000, Colomer et al 2006] 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 ComplicationsDaily 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. SurveillanceScoliosis 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 AvoidObesity is to be avoided because it makes walking more difficult.Medications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:Definite high risk. Vinca alkaloids (Vincristine)This category should be avoided by all persons with CMT, including those who are asymptomaticOther potential risk levels. See Table 5. For more information, click here (pdf).Table 5. Medications Potentially Toxic to Persons with CMTView in own windowModerate to Significant Risk 1- Amiodarone (Cordarone) - Bortezomib (Velcade) - Cisplatin & Oxaliplatin - Colchicine (extended use) - Dapsone - Didanosine (ddI, Videx) - Dichloroacetate - Disulfiram (Antabuse) - Gold salts - Leflunomide (Arava) - Metronidazole/Misonidazole (extended use) - Nitrofurantoin (Macrodantin, Furadantin, Macrobid) - Nitrous oxide (inhalation abuse or Vitamin B12 deficiency) - Perhexiline (not used in U.S.) - Pyridoxine (mega dose of Vitamin B6) - Stavudine (d4T, Zerit) - Suramin - Taxols (paclitaxel, docetaxel) - Thalidomide - Zalcitabine (ddC, Hivid)Click here (pdf) for additional medications in lesser-risk categories.The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996], Nishikawa et al [2008], and Porter et al [2009]Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSee Grandis & Shy [2005].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherCareer 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCMT4CSH3TC25q32SH3 domain and tetratricopeptide repeats-containing protein 2IPN Mutations, SH3TC2 SH3TC2 homepage - Leiden Muscular Dystrophy pagesSH3TC2Data 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) View in own window 601596CHARCOT-MARIE-TOOTH DISEASE, TYPE 4C; CMT4C 608206SH3 DOMAIN AND TETRATRICOPEPTIDE REPEAT DOMAIN 2; SH3TC2Normal allelic variants. The normal gene comprises 17 coding exons spanning 62 kb of genomic sequence. Pathologic allelic variants. To date, 20 mutations have been reported [Senderek et al 2003, Azzedine et al 2005, Azzedine et al 2006, Colomer et al 2006]. See Table 6. Table 6. Selected SH3TC2 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference Sequencesc.28delG (26delG)p.Glu10Serfs*4 (Arg9fs)NM_024577.3 NP_078853.2 c.217_227delGCTGCTCGGAGinsCCAGTAAp.Ala73Profs*55c.530-2A>G-- 2 c.920G>Ap. Trp307*c.1178-1G>A-- 2 c.1586G>Ap.Arg529Glnc.1747_1748delAGp.Arg583Alafs*4c.1969G>Ap.Glu657Lysc.1972C>Tp.Arg658Cysc.1982T>Cp.Leu662Proc.2191delGp.Glu731Lysfs*20c.2491_2492delAGp.Leu832Hisfs*8 c.2642A>Tp.Asn881Serc.2710C>Tp. Arg904*c.2829T>Gp.Tyr943*c.2860C>Tp.Arg954*c.3325C>Tp.Arg1109*c.3326G>Cp.Arg1109Proc.3341delCp.Pro1114Leufs*2c.3601C>Tp.Gln1201*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). For frameshift mutations, '*#' indicates the codon position in the new reading frame that ends in a stop (*). 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 (*#), e.g., p.Glu10Serfs*4). The shifted reading frame is thus open for '#-1' amino acids (thus in p.Glu10Serfs*4, 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 mutations in SH3TC2 lead to loss or truncation of the protein, compatible with loss of function in an autosomal recessive disease. Thirteen of the 19 mutations 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.Arg904* mutation 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.Gln1201* mutation reported by Senderek et al [2003] was sufficient to induce the phenotype.