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M M Reilly - One of the best experts on this subject based on the ideXlab platform.
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haplotype specific modulation of a sox10 creb response element at the charcot marie tooth disease type 4c locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, M M Reilly, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
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the phenotype of charcot marie tooth disease type 4c due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy
Neuromuscular Disorders, 2009Co-Authors: Henry Houlden, M Laura, L Ginsberg, Heinz Jungbluth, Stephanie Robb, J Blake, Susan Robinson, R H M King, M M ReillyAbstract:Abstract Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.
Byung Ok Choi - One of the best experts on this subject based on the ideXlab platform.
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Compound heterozygous mutations of SH3TC2 in Charcot–Marie–Tooth disease type 4C patients
Journal of Human Genetics, 2019Co-Authors: Ah Jin Lee, Soo Hyun Nam, Jin-mo Park, Sumaira Kanwal, Yu Jin Choi, Hyun Jung Lee, Kyung Suk Lee, Ji Eun Lee, Jin-sung Park, Byung Ok ChoiAbstract:Charcot–Marie–Tooth disease type 4C (CMT4C) is an autosomal recessive neuropathy caused by SH3TC2 mutations, characterized by spine deformities and cranial nerve involvement. This study identified four CMT4C families with compound heterozygous SH3TC2 mutations from 504 Korean demyelinating or intermediate CMT patients. The frequency of the CMT4C was calculated as 0.79% in demyelinating and intermediate patients ( n = 504), but it was calculated as 2.02% in patients without PMP22 duplication ( n = 198). The CMT4C frequency was similar to patients in Japan, but it was relatively low compared to those patients in other populations. The symptom was less severe and slowly progressed compared to the other AR-CMT. A patient harboring an intermediate neuropathy showed cranial nerve involvement but did not have scoliosis. This study will be helpful in making molecular diagnoses of demyelinating or intermediate CMT due to SH3TC2 mutations.
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Compound heterozygous mutations of SH3TC2 in Charcot-Marie-Tooth disease type 4C patients.
Journal of Human Genetics, 2019Co-Authors: Ah Jin Lee, Soo Hyun Nam, Jin-mo Park, Sumaira Kanwal, Yu Jin Choi, Hyun Jung Lee, Kyung Suk Lee, Ji Eun Lee, Jin-sung Park, Byung Ok ChoiAbstract:Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive neuropathy caused by SH3TC2 mutations, characterized by spine deformities and cranial nerve involvement. This study identified four CMT4C families with compound heterozygous SH3TC2 mutations from 504 Korean demyelinating or intermediate CMT patients. The frequency of the CMT4C was calculated as 0.79% in demyelinating and intermediate patients (n = 504), but it was calculated as 2.02% in patients without PMP22 duplication (n = 198). The CMT4C frequency was similar to patients in Japan, but it was relatively low compared to those patients in other populations. The symptom was less severe and slowly progressed compared to the other AR-CMT. A patient harboring an intermediate neuropathy showed cranial nerve involvement but did not have scoliosis. This study will be helpful in making molecular diagnoses of demyelinating or intermediate CMT due to SH3TC2 mutations.
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haplotype specific modulation of a sox10 creb response element at the charcot marie tooth disease type 4c locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, M M Reilly, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
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Haplotype-Specific Modulation of a SOX10/CREB Response Element at the Charcot-Marie-Tooth Disease Type 4C Locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Mary M. Reilly, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
John Svaren - One of the best experts on this subject based on the ideXlab platform.
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haplotype specific modulation of a sox10 creb response element at the charcot marie tooth disease type 4c locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, M M Reilly, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
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Haplotype-Specific Modulation of a SOX10/CREB Response Element at the Charcot-Marie-Tooth Disease Type 4C Locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Mary M. Reilly, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
James R Lupski - One of the best experts on this subject based on the ideXlab platform.
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Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy
Genome Medicine, 2013Co-Authors: James R Lupski, Claudia Gonzaga-jauregui, Matthew N Bainbridge, Yaping Yang, Shalini Jhangiani, Christian J Buhay, Christie L Kovar, Min Wang, Alicia C Hawes, Jeffrey G ReidAbstract:Background The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation. Methods We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq). Results We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband. Conclusions ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals.
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Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy
Genome Medicine, 2013Co-Authors: James R Lupski, Claudia Gonzaga-jauregui, Matthew N Bainbridge, Yaping Yang, Shalini Jhangiani, Christian J Buhay, Christie L Kovar, Min Wang, Alicia Hawes, Jeffrey G ReidAbstract:The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation. We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq). We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband. ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals.
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whole genome sequencing in a patient with charcot marie tooth neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, David Rio Deiros, Huyen Dinh, Chyn Jing, Lynne V Nazareth, Claudia Gonzagajauregui, David A Wheeler, Matthew N Bainbridge, J G Reid, Amy L. McguireAbstract:BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
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Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, David Rio Deiros, Huyen Dinh, Chyn Jing, Lynne V Nazareth, Claudia Gonzaga-jauregui, David A Wheeler, Matthew N Bainbridge, Jeffrey S Reid, Amy L. McguireAbstract:BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
Michael E. Shy - One of the best experts on this subject based on the ideXlab platform.
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Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease
Neurology, 2019Co-Authors: A Cortese, Alexander M. Rossor, M Laura, Janel E. Wilcox, James M. Polke, Roy Poh, M Skorupinska, Pedro J. Tomaselli, H Houlden, Michael E. ShyAbstract:Objective To investigate the effectiveness of targeted next-generation sequencing (NGS) panels in achieving a molecular diagnosis in Charcot-Marie-Tooth disease (CMT) and related disorders in a clinical setting. Methods We prospectively enrolled 220 patients from 2 tertiary referral centers, one in London, United Kingdom (n = 120), and one in Iowa (n = 100), in whom a targeted CMT NGS panel had been requested as a diagnostic test. PMP22 duplication/deletion was previously excluded in demyelinating cases. We reviewed the genetic and clinical data upon completion of the diagnostic process. Results After targeted NGS sequencing, a definite molecular diagnosis, defined as a pathogenic or likely pathogenic variant, was reached in 30% of cases (n = 67). The diagnostic rate was similar in London (32%) and Iowa (29%). Variants of unknown significance were found in an additional 33% of cases. Mutations in GJB1, MFN2, and MPZ accounted for 39% of cases that received genetic confirmation, while the remainder of positive cases had mutations in diverse genes, including SH3TC2, GDAP1, IGHMBP2, LRSAM1, FDG4, and GARS, and another 12 less common genes. Copy number changes in PMP22, MPZ, MFN2, SH3TC2, and FDG4 were also accurately detected. A definite genetic diagnosis was more likely in cases with an early onset, a positive family history of neuropathy or consanguinity, and a demyelinating neuropathy. Conclusions NGS panels are effective tools in the diagnosis of CMT, leading to genetic confirmation in one-third of cases negative for PMP22 duplication/deletion, thus highlighting how rarer and previously undiagnosed subtypes represent a relevant part of the genetic landscape of CMT.
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Charcot–Marie–Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges
Muscle & Nerve, 2017Co-Authors: Nivedita U. Jerath, Christopher Grunseich, Alice B. Schindler, Ami Mankodi, Hasna Baloui, Chioma Nnamdi-emeratom, Roman Chrast, Thomas O. Crawford, Terry Heiman-patterson, Michael E. ShyAbstract:INTRODUCTION This study analyzes and describes atypical presentations of Charcot-Marie-Tooth disease type 4C (CMT4C). METHODS We present clinical and physiologic features of 5 patients with CMT4C caused by biallelic private mutations of SH3TC2. RESULTS All patients manifested scoliosis, and nerve conduction study indicated results in the demyelinating range. All patients exhibited signs of motor impairment within the first years of life. We describe 2 or more different genetic diseases in the same patient, atypical presentations of CMT, and 3 new mutations in CMT4C patients. DISCUSSION A new era of unbiased genetic testing has led to this small case series of individuals with CMT4C and highlights the recognition of different genetic diseases in CMT4C patients for accurate diagnosis, genetic risk identification, and therapeutic intervention. The phenotype of CMT4C, in addition, appears to be enriched by a number of features unusual for the broad CMT category. Muscle Nerve 57: 749-755, 2018.
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Diagnostic Challenges due to Atypical presentations of CMT in Charcot Marie Tooth Disease type 4C associated with SH3TC2 mutations (P5.124)
Neurology, 2017Co-Authors: Nivedita U. Jerath, Christopher Grunseich, Alice B. Schindler, Michael E. Shy, Hasna Baloui, Chioma Nnamdi-emeratom, Roman Chrast, Ami MankodiAbstract:Objective: To analyze and describe atypical presentations of CMT 4C. Background: CMT4C is associated with both nonsense and missense mutations in the gene encoding the SH3 domain and tetratricopeptide repeats (SH3TC2), which is essential for peripheral nerve myelination. The clinical spectrum of CMT4C is suggested to be broad with likely mutation-specific variation. Previous reports have suggested that common features of CMT4C include thoracic spine scoliosis , moderate to severe neuropathy, and cranial nerve deficits such as cranial nerves 3, 7, 8, 12. Here we report four patients with atypical phenotypes associated with novel and rare SH3TC2 mutations and review previous published cases in the literature. Design/Methods: We present a case series comprised of four patients in whom CMT 4C is caused by either a novel or a rare mutation in the SH3TC2 gene. We focus on clinical presentation and electrodiagnostic analysis. Previous reported cases have also been analyzed. Results: Four unrelated patients with CMT 4C carrying disease causing SH3TC2 mutations were identified. Nerve conduction velocities were all in the demyelinating range and all had scoliosis. Age of onset of symptoms was at birth in three out of our four cases. Some cases presented with features atypical of classic CMT: nystagmus, dysarthria, attacks of weakness and sensory loss, and proximal limb girdle weakness. Conclusions: Our results suggest that certain mutations in the SH3TC2 gene can present with clinical features atypical of classic presentations of CMT. These atypical features have been described previously, and our results confirm the diagnostic challenge associated with CMT 4C. Study Supported by: This work was supported by intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS), NIH (AM). The work was supported by a grant from the National Institute of Neurological Disorders and Stroke (MES) and Office of Rare Diseases (MES, U54NS065712), Muscular Dystrophy Association (MES), Charcot-Marie-Tooth Association (MES), and MDA Clinical Research Training grant (NUJ). Disclosure: Dr. Jerath has nothing to disclose. Dr. Grunseich has nothing to disclose. Dr. Baloui has nothing to disclose. Dr. Nnamdi-Emeratom has nothing to disclose. Dr. Schindler has nothing to disclose. Dr. Chrast has nothing to disclose. Dr. Shy has nothing to disclose. Dr. Mankodi has nothing to disclose.
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haplotype specific modulation of a sox10 creb response element at the charcot marie tooth disease type 4c locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, M M Reilly, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.
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Haplotype-Specific Modulation of a SOX10/CREB Response Element at the Charcot-Marie-Tooth Disease Type 4C Locus SH3TC2
Human Molecular Genetics, 2014Co-Authors: Megan H. Brewer, Mary M. Reilly, Ki H., Gary W. Beecham, Chetna Gopinath, Frank Baas, Byung Ok Choi, Michael E. Shy, Stephan Züchner, John SvarenAbstract:Loss-of-function mutations in the Src homology 3 (SH3) domain and tetratricopeptide repeats 2 (SH3TC2) gene cause autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy. The SH3TC2 protein has been implicated in promyelination signaling through axonal neuregulin-1 and the ERBB2 Schwann cell receptor. However, little is known about the transcriptional regulation of the SH3TC2 gene. We performed computational and functional analyses that revealed two cis-acting regulatory elements at SH3TC2-one at the promoter and one ∼150 kb downstream of the transcription start site. Both elements direct reporter gene expression in Schwann cells and are responsive to the transcription factor SOX10, which is essential for peripheral nervous system myelination. The downstream enhancer harbors a single-nucleotide polymorphism (SNP) that causes an ∼80% reduction in enhancer activity. The SNP resides directly within a predicted binding site for the transcription factor cAMP response element binding protein (CREB), and we demonstrate that this regulatory element binds to CREB and is activated by CREB expression. Finally, forskolin induces SH3TC2 expression in rat primary Schwann cells, indicating that SH3TC2 is a CREB target gene. These findings prompted us to determine if SNP genotypes at SH3TC2 are associated with differential phenotypes in the most common demyelinating peripheral neuropathy, CMT1A. Interestingly, this revealed several associations between SNP alleles and disease severity. In summary, our data indicate that SH3TC2 is regulated by the transcription factors CREB and SOX10, define a regulatory SNP at this disease-associated locus and reveal SH3TC2 as a candidate modifier locus of CMT disease phenotypes.