Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy

Jan Senderek, Carsten Bergmann, Claudia Stendel, Jutta Kirfel, Nathalie Verpoorten, Peter De Jonghe, Vincent Timmerman, Roman Chrast, Mark H G Verheijen, Greg Lemke, Esra Battaloglu, Yesim Parman, Sevim Erdem, Ersin Tan, Haluk Topaloglu, Andreas Hahn, Wolfgang Müller-Felber, Nicolò Rizzuto, Gian Maria Fabrizi, Manfred StuhrmannSabine Rudnik-Schöneborn, Stephan L Zuchner, J. Michael Schröder, Eckhard Buchheim, Volker Straub, Jörg Klepper, Kathrin Huehne, Bernd Rautenstrauss, Reinhard Büttner, Eva Nelis, Klaus Zerres

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

Original languageEnglish
Pages (from-to)1106-1119
Number of pages14
JournalAmerican Journal of Human Genetics
Volume73
Issue number5
DOIs
StatePublished - Nov 1 2003
Externally publishedYes

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src Homology Domains
Mutation
Genes
Proteins
Hereditary Sensory and Motor Neuropathy
Alleles
Nerve Tissue
Sequence Alignment
Schwann Cells
Scoliosis
Missense Mutation
Peripheral Nerves
Vertebrates
Chromosomes
Type 4C Charcot-Marie-Tooth disease
Pathology
Amino Acids

ASJC Scopus subject areas

  • Genetics

Cite this

Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P., ... Zerres, K. (2003). Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy. American Journal of Human Genetics, 73(5), 1106-1119. https://doi.org/10.1086/379525

Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy. / Senderek, Jan; Bergmann, Carsten; Stendel, Claudia; Kirfel, Jutta; Verpoorten, Nathalie; De Jonghe, Peter; Timmerman, Vincent; Chrast, Roman; Verheijen, Mark H G; Lemke, Greg; Battaloglu, Esra; Parman, Yesim; Erdem, Sevim; Tan, Ersin; Topaloglu, Haluk; Hahn, Andreas; Müller-Felber, Wolfgang; Rizzuto, Nicolò; Fabrizi, Gian Maria; Stuhrmann, Manfred; Rudnik-Schöneborn, Sabine; Zuchner, Stephan L; Schröder, J. Michael; Buchheim, Eckhard; Straub, Volker; Klepper, Jörg; Huehne, Kathrin; Rautenstrauss, Bernd; Büttner, Reinhard; Nelis, Eva; Zerres, Klaus.

In: American Journal of Human Genetics, Vol. 73, No. 5, 01.11.2003, p. 1106-1119.

Research output: Contribution to journalArticle

Senderek, J, Bergmann, C, Stendel, C, Kirfel, J, Verpoorten, N, De Jonghe, P, Timmerman, V, Chrast, R, Verheijen, MHG, Lemke, G, Battaloglu, E, Parman, Y, Erdem, S, Tan, E, Topaloglu, H, Hahn, A, Müller-Felber, W, Rizzuto, N, Fabrizi, GM, Stuhrmann, M, Rudnik-Schöneborn, S, Zuchner, SL, Schröder, JM, Buchheim, E, Straub, V, Klepper, J, Huehne, K, Rautenstrauss, B, Büttner, R, Nelis, E & Zerres, K 2003, 'Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy', American Journal of Human Genetics, vol. 73, no. 5, pp. 1106-1119. https://doi.org/10.1086/379525
Senderek, Jan ; Bergmann, Carsten ; Stendel, Claudia ; Kirfel, Jutta ; Verpoorten, Nathalie ; De Jonghe, Peter ; Timmerman, Vincent ; Chrast, Roman ; Verheijen, Mark H G ; Lemke, Greg ; Battaloglu, Esra ; Parman, Yesim ; Erdem, Sevim ; Tan, Ersin ; Topaloglu, Haluk ; Hahn, Andreas ; Müller-Felber, Wolfgang ; Rizzuto, Nicolò ; Fabrizi, Gian Maria ; Stuhrmann, Manfred ; Rudnik-Schöneborn, Sabine ; Zuchner, Stephan L ; Schröder, J. Michael ; Buchheim, Eckhard ; Straub, Volker ; Klepper, Jörg ; Huehne, Kathrin ; Rautenstrauss, Bernd ; Büttner, Reinhard ; Nelis, Eva ; Zerres, Klaus. / Mutations in a Gene Encoding a Novel SH3/TPR Domain Protein Cause Autosomal Recessive Charcot-Marie-Tooth Type 4C Neuropathy. In: American Journal of Human Genetics. 2003 ; Vol. 73, No. 5. pp. 1106-1119.
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abstract = "Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.",
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AU - Bergmann, Carsten

AU - Stendel, Claudia

AU - Kirfel, Jutta

AU - Verpoorten, Nathalie

AU - De Jonghe, Peter

AU - Timmerman, Vincent

AU - Chrast, Roman

AU - Verheijen, Mark H G

AU - Lemke, Greg

AU - Battaloglu, Esra

AU - Parman, Yesim

AU - Erdem, Sevim

AU - Tan, Ersin

AU - Topaloglu, Haluk

AU - Hahn, Andreas

AU - Müller-Felber, Wolfgang

AU - Rizzuto, Nicolò

AU - Fabrizi, Gian Maria

AU - Stuhrmann, Manfred

AU - Rudnik-Schöneborn, Sabine

AU - Zuchner, Stephan L

AU - Schröder, J. Michael

AU - Buchheim, Eckhard

AU - Straub, Volker

AU - Klepper, Jörg

AU - Huehne, Kathrin

AU - Rautenstrauss, Bernd

AU - Büttner, Reinhard

AU - Nelis, Eva

AU - Zerres, Klaus

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N2 - Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

AB - Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.

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