Alternative titles; symbols
HGNC Approved Gene Symbol: SH3TC2
SNOMEDCT: 715797002;
Cytogenetic location: 5q32 Genomic coordinates (GRCh38) : 5:148,982,150-149,063,062 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Charcot-Marie-Tooth disease, type 4C | 601596 | Autosomal recessive | 3 |
| Mononeuropathy of the median nerve, mild | 613353 | Autosomal dominant | 3 |
The SH3TC2 gene encodes a protein expressed in Schwann cells of peripheral nerves, and localized to the plasma membrane and to the perinuclear endocytic recycling compartment, suggesting a possible function in myelination and/or in regions of axoglial interactions (Arnaud et al., 2009).
By sequencing clones derived from a human adult hippocampus cDNA library, Nagase et al. (2001) cloned the full-length SH3TC2 gene, which they called KIAA1985. The transcript contains multiple SINEs in the 5-prime and 3-prime untranslated regions. The longest ORF predicted a 955-amino acid protein. RT-PCR ELISA detected expression in adult heart, testis, spinal cord, and brain as well as in fetal brain and liver. Expression was found in all specific regions of the brain examined. Little or no expression was detected in adult lung, liver, skeletal muscle, kidney, pancreas, spleen, or ovary.
Senderek et al. (2003) determined that the KIAA1985 sequence predicts a 1,288-amino acid protein with a calculated molecular mass of 144.7 kD. The human protein shares 81% amino acid homology with the murine ortholog. Using Northern blot analysis, Senderek et al. (2003) showed expression of a 7.5-kb KIAA1985 transcript to be strong in brain and spinal cord, and weak in striated muscle. RT-PCR showed expression in sciatic nerve and spinal cord. A smaller transcript of 4.5 kb was also detected, suggesting alternative splicing. Further analysis of the protein indicated the presence of 2 N-terminal Src homology-3 (SH3) domains and 10 tetratricopeptide repeat (TPR) motifs arranged in tandem arrays.
Senderek et al. (2003) determined that the SH3TC2 gene contains 18 exons.
Roberts et al. (2010) showed that wildtype SH3TC2 localizes to the intracellular recycling endosome by associating with the small GTPase Rab11 (605570), which regulates the recycling of internalized membrane and receptors back to the plasma membrane. SH3TC2 interacted preferentially with the GTP-bound form of Rab11, suggesting that SH3TC2 may be a novel Rab11 effector. All SH3TC2 constructs harboring disease-causing mutations were unable to associate with Rab11, with consequent loss of recycling endosome localization. Wildtype, but not mutant, SH3TC2 influenced transferrin receptor (190010) dynamics, consistent with a functional role on the endocytic recycling pathway. The authors hypothesized that mistargeting of SH3TC2 away from the recycling endosome may be the fundamental molecular defect in Charcot-Marie-Tooth disease type 4C (CMT4C; 601596).
Using computational and functional analyses, Brewer et al. (2014) identified regulatory elements in the SH3TC2 gene that are conserved across several mammalian species. A head-to-head SOX10 (602229)-binding site in the proximal promoter region induced expression of an SH3TC2 reporter in both transfected S16 immortalized rat Schwann cells and MN-1 mouse motor neurons. Approximately 150 kb downstream of the transcription start site, Brewer et al. (2014) identified a monomeric SOX10 consensus sequence separated by 7 bp from a CREB (see 123810)-binding site. This SOX10-CREB element functioned as an enhancer, and SOX10 and CREB activated SH3TC2 expression from this site in a synergistic manner.
Stumpf (2020) mapped the SH3TC2 gene to chromosome 5q32 based on an alignment of the SH3TC2 sequence (GenBank BC113879) with the genomic sequence (GRCh38).
Charcot-Marie-Tooth Disease Type 4C
In affected members of 11 families and 1 sporadic patient with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified 11 different mutations in the SH3TC2 gene (see 608206.0001-608206.0005), 7 of which occurred in exon 11.
Gooding et al. (2005) identified a homozygous mutation in the SH3TC2 gene (R1109X; 608206.0006) in 12 patients with CMT4C from European Gypsy families, of whom 8 were from a large Spanish Gypsy kindred. Haplotype analysis indicated a founder effect with a conserved ancestral segment of approximately 0.6 cM. Among Spanish Gypsies, the carrier rate of R1109X was estimated at 1 in 26.
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.
Lupo et al. (2009) demonstrated that the SH3TC2 protein was present in several components of the endocytic pathway including early endosomes, late endosomes, and clathrin-coated vesicles close to the trans-Golgi network and in the plasma membrane of COS-7 cells. Myristoylation of SH3TC2 at residue gly2 was necessary but not sufficient for the proper location of the protein in cell membranes. In addition to myristoylation, correct anchoring also required the presence of either SH3 or TPR domains in combination with myristoylation. Mutations, such as R954X and R1109X, that caused a stop codon and produced premature terminations removing most of the C-terminal TPR domains resulted in an expression pattern that was the same as wildtype protein. In contrast, missense mutations, such as R529Q (608206.0001) and E657K (602806.0007), in or around the region of the first TPR domain were absent from early endosomes, reduced in plasma membrane and late endosomes, and were variably present in clathrin-coated vesicles. Lupo et al. (2009) suggested that the endocytic and membrane trafficking pathway may be involved in the pathogenesis of CMT4C disease, and that missense mutations of SH3TC2 could impair communication between the Schwann cell and the axon causing abnormal myelin formation.
Mild Mononeuropathy of the Median Nerve
Lupski et al. (2010) reported a 3-generation family with variable severity of a peripheral neuropathy. The family was ascertained through 4 sibs with phenotype consistent with autosomal recessive CMT4C caused by compound heterozygous mutations in the SH3TC2 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 subtle mild mononeuropathy of the median nerve (MNMN; 613353) consistent with carpal tunnel syndrome. This involvement of the median nerve was also seen in the patients with CMT4C. Lupski et al. (2010) concluded that haploinsufficiency of SH3TC2 may confer susceptibility to carpal tunnel syndrome. Two additional family members who were heterozygous for the Y169H mutation had an apparently autosomal dominant patchy axonal polyneuropathy, as shown by electrophysiologic studies, with definite median-nerve mononeuropathy at the wrist associated with evidence of a more widespread axonal neuropathy. The phenotype was similar to that of hereditary neuropathy with liability to pressure palsies (HNPP; 162500). The authors postulated a toxic gain of function for the Y169H-mutant protein. Lupski et al. (2010) commented on the subtle apparently autosomal dominant phenotypes segregating independently with the respective SH3TC2 mutations.
Regulatory Polymorphisms
Brewer et al. (2014) identified a C-T SNP, rs1759452, within a distal enhancer approximately 150 kb downstream of the transcription start site of SH3TC2. The minor allele (T) of the SNP reduced SH3TC2 reporter activity by approximately 80% due to disruption of a CREB-binding site.
Arnaud et al. (2009) found that Sh3tc2-null mice developed a progressive peripheral neuropathy manifest by decreased motor and sensory nerve conduction velocity and hypomyelination. Murine Sh3tc2 was specifically expressed in Schwann cells and localized to the plasma membrane and to the perinuclear endocytic recycling compartment, suggesting a possible function in myelination and/or in regions of axoglial interactions. Analysis of myelin in the peripheral nerve of mutant mice showed abnormal organization of the node of Ranvier, a phenotype that was confirmed in CMT4C patient nerve biopsies. The findings suggested a role for the SH3TC2 gene product in myelination and in the integrity of the node of Ranvier.
In 2 unrelated Turkish patients with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), both from consanguineous families, Senderek et al. (2003) identified a homozygous 1586G-A transition in exon 11 of the SH3TC2 gene, resulting in an arg529-to-gln (R529Q) substitution. The R529Q mutation was also detected in heterozygous state in 1 of 320 Turkish control chromosomes.
In 2 unrelated Turkish patients with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), both from consanguineous families, Senderek et al. (2003) identified a homozygous 2-bp deletion in exon 11 of the SH3TC2 gene, 1747delAG, resulting in a frameshift and premature stop codon at residue 586.
In 4 affected individuals from a consanguineous Italian family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified homozygosity for an A-to-G transition in a splice site (IVS5-2A-G), predicted to result in exon skipping.
In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense mutations in exon 11 of the SH3TC2 gene: a 2829T-G transversion, resulting in a tyr943-to-ter (Y943X) mutation, and the R954X mutation (608206.0005).
In 3 affected sibs from a German family with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Senderek et al. (2003) identified compound heterozygosity for 2 nonsense mutations in exon 11 of the SH3TC2 gene: a 2860C-T transition, resulting in an arg954-to-ter mutation (R954X; 608206.0005), and the Y943X mutation (608206.0004).
Azzedine et al. (2006) reported that the R954X mutation was recurrent in their patient series, identified in 4 Dutch families and 1 Algerian family with CMT4C.
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 a 1969G-A transition, resulting in a gly657-to-lys substitution (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.
In 4 sibs with CMT4C, Lupski et al. (2010) identified compound heterozygosity for 2 mutations in the SH3TC2 gene: R954X and Y169H (608206.0008). Three additional family members who were heterozygous for the R954X mutation had a mild mononeuropathy of the median nerve (MNMN; 613353) consistent with carpal tunnel syndrome. Lupski et al. (2010) concluded that haploinsufficiency of SH3TC2 may confer susceptibility to carpal tunnel syndrome.
In 12 patients with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596) from European Gypsy families, Gooding et al. (2005) identified a homozygous 3325C-T (genomic position 52751) transition in exon 14 of the SH3TC2 gene, resulting in an arg1109-to-ter (R1109X) substitution near the C-terminal domain of the protein. Eight of the patients came from a large Spanish Gypsy kindred. Haplotype analysis indicated a founder effect with a conserved ancestral segment of approximately 0.6 cM. Among Spanish Gypsies, the carrier rate of R1109X was estimated at 1 in 26.
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.
For discussion of the glu657-to-lys (E657K) mutation in the SH3TC2 gene that was found in compound heterozygous state in patients with Charcot-Marie-Tooth disease type 4C (CMT4C; 601596) by Houlden et al. (2009), see 608206.0005.
In sibs with autosomal recessive Charcot-Marie-Tooth disease type 4C (CMT4C; 601596), Lupski et al. (2010) identified compound heterozygosity for 2 mutations in the SH3TC2 gene: an A-to-G transition, resulting in a tyr169-to-his (Y169H) substitution and R954X (608206.0005). Two other family members who were heterozygous for the Y169H mutation had an apparently autosomal dominant patchy axonal neuropathy with median nerve mononeuropathy at the wrist (MNMN; 613353), as shown by electrophysiologic studies. These findings suggested a toxic gain of function for the mutant protein, and indicated that heterozygous SH3TC2 mutation carriers may also have a phenotype.
Arnaud, E., Zenker, J., de Preux Charles, A.-S., Stendel, C., Roos, A., Medard, J.-J., Tricaud, N., Kleine, H., Luscher, B., Weis, J., Suter, U., Senderek, J., Chrast, R. SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. Proc. Nat. Acad. Sci. 106: 17528-17533, 2009. Note: Erratum: Proc. Nat. Acad. Sci. 107: 15305 only, 2010. [PubMed: 19805030] [Full Text: https://doi.org/10.1073/pnas.0905523106]
Azzedine, H., Ravise, N., Verny, C., Gabreels-Festen, A., Lammens, M., Grid, D., Vallat, J. M., Durosier, G., Senderek, J., Nouioua, S., Hamadouche, T., Bouhouche, A., Guilbot, A., Stendel, C., Ruberg, M., Brice, A., Birouk, N., Dubourg, O., Tazir, M., LeGuern, E. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 67: 602-606, 2006. [PubMed: 16924012] [Full Text: https://doi.org/10.1212/01.wnl.0000230225.19797.93]
Brewer, M. H., Ma, K. H., Beecham, G. W., Gopinath, C., the Inherited Neuropathy Consortium (INC), Baas, F., Choi, B.-O., Reilly, M. M., Shy, M. E., Zuchner, S., Svaren, J., Antonellis, A. Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4c locus SH3TC2. Hum. Molec. Genet. 23: 5171-5187, 2014. [PubMed: 24833716] [Full Text: https://doi.org/10.1093/hmg/ddu240]
Claramunt, R., Sevilla, T., Lupo, V., Cuesta, A., Millan, J.M., Vilchez, J. J., Palau, F., Espinos, C. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin. Genet. 71: 343-349, 2007. [PubMed: 17470135] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00774.x]
Gooding, R., Colomer, J., King, R., Angelicheva, D., Marns, L., Parman, Y., Chandler, D., Bertranpetit, J., Kalaydjieva, L. A novel Gypsy founder mutation, pArg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes. J. Med. Genet. 42: e69, 2005. Note: Electronic Article. [PubMed: 16326826] [Full Text: https://doi.org/10.1136/jmg.2005.034132]
Gosselin, I., Thiffault, I., Tetreault, M., Chau, V., Dicaire, M.-J., Loisel, L., Emond, M., Senderek, J., Mathieu, J., Dupre, N., Vanasse, M., Puymirat, J., Brais, B. Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster. Neuromusc. Disord. 18: 483-492, 2008. [PubMed: 18511281] [Full Text: https://doi.org/10.1016/j.nmd.2008.04.001]
Houlden, H., Laura, M., Ginsberg, L., Jungbluth, H., Robb, S. A., Blake, J., Robinson, S., King, R. H. M., Reilly, M. M. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy. Neuromusc. Disord. 19: 264-269, 2009. [PubMed: 19272779] [Full Text: https://doi.org/10.1016/j.nmd.2009.01.006]
Lupo, V., Galindo, M. I., Martinez-Rubio, D., Sevilla, T., Vilchez, J. J., Palau, F., Espinos, C. Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway. Hum. Molec. Genet. 18: 4603-4614, 2009. [PubMed: 19744956] [Full Text: https://doi.org/10.1093/hmg/ddp427]
Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C. Y., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D. A., McGuire, A. L., Zhang, F., and 10 others. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. New Eng. J. Med. 362: 1181-1191, 2010. [PubMed: 20220177] [Full Text: https://doi.org/10.1056/NEJMoa0908094]
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res. 8: 319-327, 2001. [PubMed: 11853319] [Full Text: https://doi.org/10.1093/dnares/8.6.319]
Roberts, R. C., Peden, A. A., Buss, F., Bright, N. A., Latouche, M., Reilly, M. M., Kendrick-Jones, J., Luzio, J. P. Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C. Hum. Molec. Genet. 19: 1009-1018, 2010. [PubMed: 20028792] [Full Text: https://doi.org/10.1093/hmg/ddp565]
Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P., Timmerman, V., Chrast, R., Verheijen, M. H. G., Lemke, G., Battaloglu, E., Parman, Y., and 19 others. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am. J. Hum. Genet. 73: 1106-1119, 2003. [PubMed: 14574644] [Full Text: https://doi.org/10.1086/379525]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/12/2020.