Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

Minttu Marttila, Vilma Lotta Lehtokari, Steven Marston, Tuula A. Nyman, Christine Barnerias, Alan H. Beggs, Enrico Bertini, Özge Ceyhan-Birsoy, Pascal Cintas, Marion Gerard, Brigitte Gilbert-Dussardier, Jacob S. Hogue, Cheryl Longman, Bruno Eymard, Moshe Frydman, Peter B. Kang, Lars Klinge, Hanna Kolski, Hans Lochmüller, Laurent MagyVéronique Manel, Michèle Mayer, Eugenio Mercuri, Kathryn N. North, Sylviane Peudenier-Robert, Helena Pihko, Frank J. Probst, Ricardo Reisin, Willie Stewart, Ana Lia Taratuto, Marianne de Visser, Ekkehard Wilichowski, John Winer, Kristen Nowak, Nigel G. Laing, Tom L. Winder, Nicole Monnier, Nigel F. Clarke, Katarina Pelin, Mikaela Grönholm, Carina Wallgren-Pettersson

Research output: Contribution to journalArticle

Abstract

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.

Original languageEnglish
Pages (from-to)779-790
Number of pages12
JournalHuman Mutation
Volume35
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Myotonia Congenita
Genetic Association Studies
Mutation
Tropomyosin
Nemaline Myopathies
Contracture
Phenotype
Congenital Structural Myopathies
Arthrogryposis
Jaw
Computer Simulation
Genes
Actins
Protein Isoforms
Skeletal Muscle
Extremities
Joints
Databases

Keywords

  • Actin
  • Congenital myopathy
  • Genotype-phenotype correlation
  • Hypercontractile phenotype
  • TPM2
  • TPM3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Marttila, M., Lehtokari, V. L., Marston, S., Nyman, T. A., Barnerias, C., Beggs, A. H., ... Wallgren-Pettersson, C. (2014). Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies. Human Mutation, 35(7), 779-790. https://doi.org/10.1002/humu.22554

Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies. / Marttila, Minttu; Lehtokari, Vilma Lotta; Marston, Steven; Nyman, Tuula A.; Barnerias, Christine; Beggs, Alan H.; Bertini, Enrico; Ceyhan-Birsoy, Özge; Cintas, Pascal; Gerard, Marion; Gilbert-Dussardier, Brigitte; Hogue, Jacob S.; Longman, Cheryl; Eymard, Bruno; Frydman, Moshe; Kang, Peter B.; Klinge, Lars; Kolski, Hanna; Lochmüller, Hans; Magy, Laurent; Manel, Véronique; Mayer, Michèle; Mercuri, Eugenio; North, Kathryn N.; Peudenier-Robert, Sylviane; Pihko, Helena; Probst, Frank J.; Reisin, Ricardo; Stewart, Willie; Taratuto, Ana Lia; de Visser, Marianne; Wilichowski, Ekkehard; Winer, John; Nowak, Kristen; Laing, Nigel G.; Winder, Tom L.; Monnier, Nicole; Clarke, Nigel F.; Pelin, Katarina; Grönholm, Mikaela; Wallgren-Pettersson, Carina.

In: Human Mutation, Vol. 35, No. 7, 2014, p. 779-790.

Research output: Contribution to journalArticle

Marttila, M, Lehtokari, VL, Marston, S, Nyman, TA, Barnerias, C, Beggs, AH, Bertini, E, Ceyhan-Birsoy, Ö, Cintas, P, Gerard, M, Gilbert-Dussardier, B, Hogue, JS, Longman, C, Eymard, B, Frydman, M, Kang, PB, Klinge, L, Kolski, H, Lochmüller, H, Magy, L, Manel, V, Mayer, M, Mercuri, E, North, KN, Peudenier-Robert, S, Pihko, H, Probst, FJ, Reisin, R, Stewart, W, Taratuto, AL, de Visser, M, Wilichowski, E, Winer, J, Nowak, K, Laing, NG, Winder, TL, Monnier, N, Clarke, NF, Pelin, K, Grönholm, M & Wallgren-Pettersson, C 2014, 'Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies', Human Mutation, vol. 35, no. 7, pp. 779-790. https://doi.org/10.1002/humu.22554
Marttila, Minttu ; Lehtokari, Vilma Lotta ; Marston, Steven ; Nyman, Tuula A. ; Barnerias, Christine ; Beggs, Alan H. ; Bertini, Enrico ; Ceyhan-Birsoy, Özge ; Cintas, Pascal ; Gerard, Marion ; Gilbert-Dussardier, Brigitte ; Hogue, Jacob S. ; Longman, Cheryl ; Eymard, Bruno ; Frydman, Moshe ; Kang, Peter B. ; Klinge, Lars ; Kolski, Hanna ; Lochmüller, Hans ; Magy, Laurent ; Manel, Véronique ; Mayer, Michèle ; Mercuri, Eugenio ; North, Kathryn N. ; Peudenier-Robert, Sylviane ; Pihko, Helena ; Probst, Frank J. ; Reisin, Ricardo ; Stewart, Willie ; Taratuto, Ana Lia ; de Visser, Marianne ; Wilichowski, Ekkehard ; Winer, John ; Nowak, Kristen ; Laing, Nigel G. ; Winder, Tom L. ; Monnier, Nicole ; Clarke, Nigel F. ; Pelin, Katarina ; Grönholm, Mikaela ; Wallgren-Pettersson, Carina. / Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies. In: Human Mutation. 2014 ; Vol. 35, No. 7. pp. 779-790.
@article{4f0332d0737a4426ab9fd3729a8db7eb,
title = "Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies",
abstract = "Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.",
keywords = "Actin, Congenital myopathy, Genotype-phenotype correlation, Hypercontractile phenotype, TPM2, TPM3",
author = "Minttu Marttila and Lehtokari, {Vilma Lotta} and Steven Marston and Nyman, {Tuula A.} and Christine Barnerias and Beggs, {Alan H.} and Enrico Bertini and {\"O}zge Ceyhan-Birsoy and Pascal Cintas and Marion Gerard and Brigitte Gilbert-Dussardier and Hogue, {Jacob S.} and Cheryl Longman and Bruno Eymard and Moshe Frydman and Kang, {Peter B.} and Lars Klinge and Hanna Kolski and Hans Lochm{\"u}ller and Laurent Magy and V{\'e}ronique Manel and Mich{\`e}le Mayer and Eugenio Mercuri and North, {Kathryn N.} and Sylviane Peudenier-Robert and Helena Pihko and Probst, {Frank J.} and Ricardo Reisin and Willie Stewart and Taratuto, {Ana Lia} and {de Visser}, Marianne and Ekkehard Wilichowski and John Winer and Kristen Nowak and Laing, {Nigel G.} and Winder, {Tom L.} and Nicole Monnier and Clarke, {Nigel F.} and Katarina Pelin and Mikaela Gr{\"o}nholm and Carina Wallgren-Pettersson",
year = "2014",
doi = "10.1002/humu.22554",
language = "English",
volume = "35",
pages = "779--790",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

AU - Marttila, Minttu

AU - Lehtokari, Vilma Lotta

AU - Marston, Steven

AU - Nyman, Tuula A.

AU - Barnerias, Christine

AU - Beggs, Alan H.

AU - Bertini, Enrico

AU - Ceyhan-Birsoy, Özge

AU - Cintas, Pascal

AU - Gerard, Marion

AU - Gilbert-Dussardier, Brigitte

AU - Hogue, Jacob S.

AU - Longman, Cheryl

AU - Eymard, Bruno

AU - Frydman, Moshe

AU - Kang, Peter B.

AU - Klinge, Lars

AU - Kolski, Hanna

AU - Lochmüller, Hans

AU - Magy, Laurent

AU - Manel, Véronique

AU - Mayer, Michèle

AU - Mercuri, Eugenio

AU - North, Kathryn N.

AU - Peudenier-Robert, Sylviane

AU - Pihko, Helena

AU - Probst, Frank J.

AU - Reisin, Ricardo

AU - Stewart, Willie

AU - Taratuto, Ana Lia

AU - de Visser, Marianne

AU - Wilichowski, Ekkehard

AU - Winer, John

AU - Nowak, Kristen

AU - Laing, Nigel G.

AU - Winder, Tom L.

AU - Monnier, Nicole

AU - Clarke, Nigel F.

AU - Pelin, Katarina

AU - Grönholm, Mikaela

AU - Wallgren-Pettersson, Carina

PY - 2014

Y1 - 2014

N2 - Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.

AB - Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.

KW - Actin

KW - Congenital myopathy

KW - Genotype-phenotype correlation

KW - Hypercontractile phenotype

KW - TPM2

KW - TPM3

UR - http://www.scopus.com/inward/record.url?scp=84902003297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902003297&partnerID=8YFLogxK

U2 - 10.1002/humu.22554

DO - 10.1002/humu.22554

M3 - Article

C2 - 24692096

AN - SCOPUS:84902003297

VL - 35

SP - 779

EP - 790

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 7

ER -