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Dieter Gläser - One of the best experts on this subject based on the ideXlab platform.
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novel SBF2 mutations and clinical spectrum of charcot marie tooth neuropathy type 4b2
Clinical Genetics, 2018Co-Authors: Petra Laššuthová, Katharina Vill, J. M. Schröder, Haluk Topaloglu, Rita Horvath, B. Bansagi, S Erdemozdamar, W Mullerfelber, Beate Schlotterweigel, Dieter GläserAbstract:Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.
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Novel SBF2 mutations and clinical spectrum of Charcot‐Marie‐Tooth neuropathy type 4B2
Clinical genetics, 2018Co-Authors: Petra Laššuthová, Katharina Vill, S. Erdem-ozdamar, J. M. Schröder, Haluk Topaloglu, Rita Horvath, Wolfgang Müller-felber, B. Bansagi, Beate Schlotter-weigel, Dieter GläserAbstract:Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.
Klaus Zerres - One of the best experts on this subject based on the ideXlab platform.
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Cloning, expression and characterization of the murine orthologue of SBF2, the gene mutated in Charcot-Marie-Tooth disease type 4B2
Gene expression patterns : GEP, 2006Co-Authors: Jutta Kirfel, Jan Senderek, Markus Moser, Anke Röper, Claudia Stendel, Carsten Bergmann, Klaus Zerres, Reinhard BuettnerAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy (HMSN) or Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. The clinical picture includes progressive distal weakness and atrophy, foot deformities, and distal sensory loss. For autosomal recessive CMT type 4B2 one locus was mapped to chromosome 11p15. Recently, mutations in SET binding factor 2 (SBF2), were identified as cause of CMT4B2. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and all disease-associated mutations known to date lead to shortened or truncated proteins, also implicating loss-of-function. Here, we describe the molecular cloning and the expression pattern of SBF2. The mRNA spans around 8 kb, and the protein shares high amino acid identity compared to the human protein suggesting a conserved function. SBF2 is encoded by 40 exons on murine chromosome 7. In situ hybridization, Northern blots and RT-analysis revealed a very broad pattern of SBF2 expression. Overexpressed epitope tagged SBF2 showed cytoplasmic distribution. Taken together, this study provides information about the mRNA expression and subcellular localization of SBF2 and as such helps in further understanding its function in development and disease.
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Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15
Human molecular genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Susanne Weber, Uwe-peter Ketelsen, Hubert Schorle, Sabine Rudnik-schöneborn, Reinhard Büttner, Eckhard Buchheim, Klaus ZerresAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.
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mutation of the SBF2 gene encoding a novel member of the myotubularin family in charcot marie tooth neuropathy type 4b2 11p15
Human Molecular Genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Susanne Weber, Uwe-peter Ketelsen, Hubert Schorle, Reinhard Büttner, Eckhard Buchheim, Sabine Rudnikschoneborn, Klaus ZerresAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.
Jan Senderek - One of the best experts on this subject based on the ideXlab platform.
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Cloning, expression and characterization of the murine orthologue of SBF2, the gene mutated in Charcot-Marie-Tooth disease type 4B2
Gene expression patterns : GEP, 2006Co-Authors: Jutta Kirfel, Jan Senderek, Markus Moser, Anke Röper, Claudia Stendel, Carsten Bergmann, Klaus Zerres, Reinhard BuettnerAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy (HMSN) or Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. The clinical picture includes progressive distal weakness and atrophy, foot deformities, and distal sensory loss. For autosomal recessive CMT type 4B2 one locus was mapped to chromosome 11p15. Recently, mutations in SET binding factor 2 (SBF2), were identified as cause of CMT4B2. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and all disease-associated mutations known to date lead to shortened or truncated proteins, also implicating loss-of-function. Here, we describe the molecular cloning and the expression pattern of SBF2. The mRNA spans around 8 kb, and the protein shares high amino acid identity compared to the human protein suggesting a conserved function. SBF2 is encoded by 40 exons on murine chromosome 7. In situ hybridization, Northern blots and RT-analysis revealed a very broad pattern of SBF2 expression. Overexpressed epitope tagged SBF2 showed cytoplasmic distribution. Taken together, this study provides information about the mRNA expression and subcellular localization of SBF2 and as such helps in further understanding its function in development and disease.
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“A splice-junction mutation in SBF2 gene causes autosomal recessive Charcot-Marie-Tooth disease (CMT4B2) in a family from southern Italy
Journal of the Peripheral Nervous System, 2004Co-Authors: Francesca Luisa Conforti, Jan Senderek, M. Muglia, Rosalucia Mazzei, Paola Valentino, Alessandra Patitucci, Francesco Bono, Angela Magariello, Teresa Sprovieri, C. BergmannAbstract:Autosomal recessive Charcot-Marie-Tooth disease type 4 (CMT4) comprises a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. At least 10 loci are responsible for autosomal recessive CMT and six genes have been identified so far. In this study, we report a small pedigree with a recessive form of CMT (CMT4B) from Southern Italy. There were six individuals in two generations with two affected subjects. We performed haplotype analysis using highly polymorphic microsatellite markers located on chromosome 11p15. Subsequently, the coding region of the SBF2 gene was sequenced by using primers flanking intron-exon boundaries. Mutational screening of SBF2 revealed a homozygous mutation in the splice-junction donor-acceptor site of intron 32 (+1GC) in the affected patients. The variation was also confirmed by digestion with restriction enzyme Alu I and it was absent in 100 control chromosomes examined. This is the first finding of a mutation in the SBF2 gene that alters the correct splicing of the gene. Furthermore, these data confirm that mutations in the SBF2 gene are causative of CMT4B2.
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Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15
Human molecular genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Susanne Weber, Uwe-peter Ketelsen, Hubert Schorle, Sabine Rudnik-schöneborn, Reinhard Büttner, Eckhard Buchheim, Klaus ZerresAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.
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mutation of the SBF2 gene encoding a novel member of the myotubularin family in charcot marie tooth neuropathy type 4b2 11p15
Human Molecular Genetics, 2003Co-Authors: Jan Senderek, Carsten Bergmann, Susanne Weber, Uwe-peter Ketelsen, Hubert Schorle, Reinhard Büttner, Eckhard Buchheim, Sabine Rudnikschoneborn, Klaus ZerresAbstract:Abstract Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.
Ueli Suter - One of the best experts on this subject based on the ideXlab platform.
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The CMT4B disease-causing proteins MTMR2 and MTMR13/SBF2 regulate AKT signalling.
Journal of cellular and molecular medicine, 2011Co-Authors: Philipp Berger, Kristian Tersar, Kurt Ballmer-hofer, Ueli SuterAbstract:Charcot-Marie-Tooth disease type 4B is caused by mutations in the genes encoding either the lipid phosphatase myotubularin-related protein-2 (MTMR2) or its regulatory binding partner MTMR13/SBF2. Mtmr2 dephosphorylates PI-3-P and PI-3,5-P2 to form phosphatidylinositol and PI-5-P, respectively, while Mtmr13/SBF2 is an enzymatically inactive member of the myotubularin protein family. We have found altered levels of the critical signalling protein AKT in mouse mutants for Mtmr2 and Mtmr13/SBF2. Thus, we analysed the influence of Mtmr2 and Mtmr13/SBF2 on signalling processes. We found that overexpression of Mtmr2 prevents the degradation of the epidermal growth factor receptor (EGFR) and leads to sustained Akt activation whereas Erk activation is not affected. Mtmr13/SBF2 counteracts the blockage of EGFR degradation without affecting prolonged Akt activation. Our data indicate that Mtmr2 and Mtmr13/SBF2 play critical roles in the sorting and modulation of cellular signalling which are likely to be disturbed in CMT4B.
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the cmt4b disease causing proteins mtmr2 and mtmr13 SBF2 regulate akt signalling
Journal of Cellular and Molecular Medicine, 2011Co-Authors: Philipp Berger, Kristian Tersar, Kurt Ballmerhofer, Ueli SuterAbstract:Charcot-Marie-Tooth disease type 4B is caused by mutations in the genes encoding either the lipid phosphatase myotubularin-related protein-2 (MTMR2) or its regulatory binding partner MTMR13/SBF2. Mtmr2 dephosphorylates PI-3-P and PI-3,5-P2 to form phosphatidylinositol and PI-5-P, respectively, while Mtmr13/SBF2 is an enzymatically inactive member of the myotubularin protein family. We have found altered levels of the critical signalling protein AKT in mouse mutants for Mtmr2 and Mtmr13/SBF2. Thus, we analysed the influence of Mtmr2 and Mtmr13/SBF2 on signalling processes. We found that overexpression of Mtmr2 prevents the degradation of the epidermal growth factor receptor (EGFR) and leads to sustained Akt activation whereas Erk activation is not affected. Mtmr13/SBF2 counteracts the blockage of EGFR degradation without affecting prolonged Akt activation. Our data indicate that Mtmr2 and Mtmr13/SBF2 play critical roles in the sorting and modulation of cellular signalling which are likely to be disturbed in CMT4B.
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mtmr13 SBF2 deficient mice an animal model for cmt4b2
Human Molecular Genetics, 2007Co-Authors: Kristian Tersar, Philipp Berger, Matthias Boentert, Sonja Bonneick, Carsten Wessig, Klaus V. Toyka, Peter Young, Ueli SuterAbstract:Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are associated with the autosomal recessive disease subtypes CMT4B1 or CMT4B2. Both forms of CMT share similar features including a demyelinating neuropathy associated with reduced nerve conduction velocity (NCV) and focally folded myelin. Consistent with a common disease mechanism, the homodimeric MTMR2 acts as a phosphoinositide D3-phosphatase with phosphatidylinositol (PtdIns) 3-phosphate and PtdIns 3,5-bisphosphate as substrates while MTMR13/SBF2 is catalytically inactive but can form a tetrameric complex with MTMR2, resulting in a strong increase of the enzymatic activity of complexed MTMR2. To prove that MTMR13/SBF2 is the disease-causing gene in CMT4B2 and to provide a suitable animal model, we have generated Mtmr13/SBF2-deficient mice. These animals reproduced myelin outfoldings and infoldings in motor and sensory peripheral nerves as the pathological hallmarks of CMT4B2, concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. Prolonged F-wave latency indicated a mild NCV impairment. Loss of Mtmr13/SBF2 did not affect the levels of its binding partner Mtmr2 and the Mtmr2-binding Dlg1/Sap97 in peripheral nerves. Mice deficient in Mtmr13/SBF2 together with known Mtmr2-deficient animals will be of major value to unravel the disease mechanism in CMT4B and to elucidate the critical functions of protein complexes that are involved in phosphoinositide-controlled processes in peripheral nerves.
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Mtmr13/SBF2-deficient mice: an animal model for CMT4B2
Human molecular genetics, 2007Co-Authors: Kristian Tersar, Philipp Berger, Matthias Boentert, Sonja Bonneick, Carsten Wessig, Klaus V. Toyka, Peter Young, Ueli SuterAbstract:Charcot-Marie-Tooth (CMT) disease denotes a large group of genetically heterogeneous hereditary motor and sensory neuropathies and ranks among the most common inherited neurological disorders. Mutations in the Myotubularin-Related Protein-2 (MTMR2) or MTMR13/Set-Binding Factor-2 (SBF2) genes are associated with the autosomal recessive disease subtypes CMT4B1 or CMT4B2. Both forms of CMT share similar features including a demyelinating neuropathy associated with reduced nerve conduction velocity (NCV) and focally folded myelin. Consistent with a common disease mechanism, the homodimeric MTMR2 acts as a phosphoinositide D3-phosphatase with phosphatidylinositol (PtdIns) 3-phosphate and PtdIns 3,5-bisphosphate as substrates while MTMR13/SBF2 is catalytically inactive but can form a tetrameric complex with MTMR2, resulting in a strong increase of the enzymatic activity of complexed MTMR2. To prove that MTMR13/SBF2 is the disease-causing gene in CMT4B2 and to provide a suitable animal model, we have generated Mtmr13/SBF2-deficient mice. These animals reproduced myelin outfoldings and infoldings in motor and sensory peripheral nerves as the pathological hallmarks of CMT4B2, concomitant with decreased motor performance. The number and complexity of myelin misfoldings increased with age, associated with axonal degeneration, and decreased compound motor action potential amplitude. Prolonged F-wave latency indicated a mild NCV impairment. Loss of Mtmr13/SBF2 did not affect the levels of its binding partner Mtmr2 and the Mtmr2-binding Dlg1/Sap97 in peripheral nerves. Mice deficient in Mtmr13/SBF2 together with known Mtmr2-deficient animals will be of major value to unravel the disease mechanism in CMT4B and to elucidate the critical functions of protein complexes that are involved in phosphoinositide-controlled processes in peripheral nerves.
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Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2
Human molecular genetics, 2006Co-Authors: Philipp Berger, Imre Berger, Christiane Schaffitzel, Kristian Tersar, Benjamin Volkmer, Ueli SuterAbstract:Mutations in myotubularin-related protein-2 (MTMR2) or MTMR13/set-binding factor-2 (SBF2) genes are responsible for the severe autosomal recessive hereditary neuropathies, Charcot-Marie-Tooth disease (CMT) types 4B1 and 4B2, both characterized by reduced nerve conduction velocities, focally folded myelin sheaths and demyelination. MTMRs form a large family of conserved dual-specific phosphatases with enzymatically active and inactive members. We show that homodimeric active Mtmr2 interacts with homodimeric inactive SBF2 in a tetrameric complex. This association dramatically increases the enzymatic activity of the complexed Mtmr2 towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Mtmr2 and SBF2 are considerably, but not completely, co-localized in the cellular cytoplasm. On membranes of large vesicles formed under hypo-osmotic conditions, SBF2 favorably competes with Mtmr2 for binding sites. Our data are consistent with a model suggesting that, at a given cellular location, Mtmr2 phosphatase activity is highly regulated, being high in the Mtmr2/SBF2 complex, moderate if Mtmr2 is not associated with SBF2 or functionally blocked by competition through SBF2 for membrane-binding sites.
Petra Laššuthová - One of the best experts on this subject based on the ideXlab platform.
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novel SBF2 mutations and clinical spectrum of charcot marie tooth neuropathy type 4b2
Clinical Genetics, 2018Co-Authors: Petra Laššuthová, Katharina Vill, J. M. Schröder, Haluk Topaloglu, Rita Horvath, B. Bansagi, S Erdemozdamar, W Mullerfelber, Beate Schlotterweigel, Dieter GläserAbstract:Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.
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Novel SBF2 mutations and clinical spectrum of Charcot‐Marie‐Tooth neuropathy type 4B2
Clinical genetics, 2018Co-Authors: Petra Laššuthová, Katharina Vill, S. Erdem-ozdamar, J. M. Schröder, Haluk Topaloglu, Rita Horvath, Wolfgang Müller-felber, B. Bansagi, Beate Schlotter-weigel, Dieter GläserAbstract:Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.
