Elsevier

Neuromuscular Disorders

Volume 19, Issue 2, February 2009, Pages 118-123
Neuromuscular Disorders

Absence of β-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

https://doi.org/10.1016/j.nmd.2008.11.009Get rights and content

Abstract

While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of β-tropomyosin not compensated by expression of other β-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.

Introduction

Dominant mutations in the TPM2 gene have been identified in these three allelic disorders: nemaline congenital myopathy (NEM4, MIM# 609285) [1], Cap disease [2], [3] and distal arthrogryposis syndrome (DA1, MIM# 108120 and DA2B, MIM# 601680) [4], [5]. Nemaline congenital myopathy is a clinically and genetically heterogeneous disorder characterized by nemaline rods within muscle fibres. Six subtypes of nemaline myopathy have been defined according to the severity and age of onset that range from lethal neonatal to mild adult onset expression [6]. Cap disease is characterized by incomplete sarcomeres with enlarged Z discs at the periphery of muscle fibres and presents many similarities with the typical form of nemaline myopathy [2]. Arthrogryposis syndromes are clinically and genetically heterogeneous disorders characterized by congenital contractures.

Tropomyosins (TM) are a family of closely related proteins that form dimeric structures interacting with actin. Multiple isoforms are expressed through the use of alternative promoters and alternative RNA splicing of four genes (TPM1TPM4) [7], [8], [9]. In mammalian striated muscle, three TM-isoforms are expressed at a level that varies with muscle and fibre types: α-TMfast (TPM1) in cardiac and fast skeletal muscles, α-TMslow (TPM3) in slow skeletal muscles and β-TM (TPM2). They localise to sarcomeric thin filaments where they play a central role in the Ca2+-dependent regulation of muscle contraction, in association with the troponin complex. TPM2 gene is located on chromosome 9 p13.2-p13.1 and comprises 9 exons among which two are alternatively and exclusively spliced: exons 6b and 9a in isoform 1 and exons 6a and 9d in isoform 2. A third isoform contains alternative exons 1b spliced to 3 , 6a and 9d. In human, β-TM isoform 1 is expressed in both fetal and adult skeletal muscle [10], isoform 2 in smooth muscle and fibroblasts [11].

Recessive forms of multiple pterygium syndrome (MPS) are clinically and genetically heterogeneous. They may result from early-onset fetal akinesia and are traditionally classified into prenatally lethal MPS and non-lethal Escobar variant-MPS (EVMPS). MPS have been recently associated with mutations in genes encoding the CHRNG, CHRNA1 or CHRND acetylcholine receptor subunits and rapsyn, a protein that play a key role in the clustering of acetylcholine receptor [12], [13], [14], [15]. EVMPS is a severe condition that presents mainly with inborn contractures, pterygia and respiratory distress (MIM# 265000).

While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report here involvement of the TPM2 gene in an autosomal recessive form of nemaline myopathy. Noticeably this recessive form is associated with EVMPS.

Section snippets

Patients and samples

Blood samples from each member of the family were collected after an inform consent was obtained. Genomic DNA was extracted using standard procedures. For family members living in Algeria, blood samples were collected and shipped on FTA® cards (Transgenomic, USA).

Histological studies

Standard staining and histoenzymatic reactions were carried out on 10 μm cross sections originating from a quadriceps muscle biopsy performed at 2 years of age in the proband. Fine sections (0.07 μm) were stained with uranyl acetate and

Clinical and pathological report

The proband (III-12) belongs to an Algerian consanguineous family (Fig. 1. panel A). He was born at term of an uneventful pregnancy and presented at birth with severe hypotonia and arthrogryposis. The child was examined for the first time at one year of age. He presented with major hypotonia, distal amyotrophy and delayed acquisition of motor milestones. Skeletal signs included scoliosis, pes varus and proximal and distal joint contractures. Neither head nor sitting control was acquired.

Discussion

In this study, we report the first case of recessive nemaline myopathy related to the TPM2 gene in a consanguineous family. Noticeably, the nemaline myopathy was associated with EVMPS in the proband. Such clinical association had been reported only once in the literature but the case was genetically and biochemically uncharacterized at the time [19].

Thin filaments in skeletal muscle are composed of αfast, αslow and β-tropomyosins whose relative amount and stoichiometry vary among muscles. In

Acknowledgements

We thank all family members for their participation in this study. We thank Mrs. S. Drouhin and J. Brocard for their technical assistance. This work was supported in part by grants from Association Française contre les Myopathies, Agence Nationale de la Recherche (ANR-Maladies Rares), Programme Hospitalier de Recherche Clinique du Centre Hospitalier Universitaire de Grenoble and from Fondation Daniel Ducoin (to J.L.).

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