Mutations in <i>TPM3</i> are a common cause of congenital fiber type disproportion

Clarke, Nigel F.; Kolski, Hannah; Dye, Danielle E.; Lim, Esther; Smith, Robert L.; Patel, Rakesh; Fahey, Michael; Bellance, Rémi; Romero, Norma B.; Johnson, Edward S.; Labarre-Vila, Annick; Monnier, Nicole; Laing, Nigel G.; North, Klaus

doi:10.1002/ana.21308

Cited by 156 publications

(88 citation statements)

References 26 publications

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“…This condition, however, is genetically heterogeneous and has been observed in several forms of congenital myopathies, neuromuscular disorders, and muscular dystrophies (Clarke and North 2003). Mutations in ACTA1 (Laing et al 2004), SEPN1 (Clarke et al 2006), TPM3 (Clarke et al 2008), RYR1 (Wilmshurst et al 2010), and more recently MYH7 (Ortolano et al 2011) have also been identified in patients with FTD. To add to its nonspecific nature, this morphological finding has been reported in association with several inherited metabolic disorders including Pompe disease (Martin et al 1976), multiple sulfatase deficiency (Tachi et al 1984), congenital lactic acidosis (Iso et al 1993), metachromatic leukodystrophy (Krendel et al 1994), carnitine palmitoyltransferase deficiency (Shintani et al 1995), and Krabbe disease (Marjanovic et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping

2011

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Congenital disorders of glycosylation (CDG) are an expanding group of genetic diseases affecting protein and lipid glycosylation. These disorders have a variable presentation and are individually rare. DPAGT1-CDG is a protein N-glycosylation disorder with epilepsy, development delay, severe hypotonia, and dysmorphy, reported in a single patient. Here we present the second family with DPAGT1-CDG identified through homozygosity mapping in a large consanguineous family with 18 affected infants. The patients had severe hypotonia, global developmental delay, seizures, and microcephaly but no dysmorphy. In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy. Homozygosity mapping identified a large block of homozygosity on chromosome 11p15.5-q25 where two known CDG-I causing genes, ALG9 and DPAGT1, are located. Sequencing ALG9 did not reveal any mutations while analysis of DPAGT1 identified a novel homozygous mutation c.902G>A (p.R301H) in two affected infants. The disorder was fatal in all affected cases and mostly in early infancy.

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Section: Discussionmentioning

confidence: 99%

Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping

2011

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“…Studies of several families with severe, intermediate and typical NM forms have identified mutations in α-tropomyosin (TPM3) and beta-tropomyosin [19][20][21] . A recent study described an Australian familly with a mutation in the TPM3 gene 22 .…”

Section: Fig 1 Hematoxilin-eosin (He) Stain Showing Variation In Fibmentioning

confidence: 99%

“…To date, defects in six distinct genes have been identified in cases of NM. These include mutations in α-tropomyosin (TPM3), betatropomyosin (TPM2), nebulin (NEB), α-actin (ACTA1), cofilin2 (CFL2) and troponin T (TNNT1) 4,[17][18][19][20][21][22][23][24][25][26][27][28] . This study describes the clinical manifestations of nemaline myopathy using histochemical analysis along with expression analysis of nebulin, desmin and myosin proteins with immunohistochemistry.…”

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confidence: 99%

Nemaline myopathy: clinical, histochemical and immunohistochemical features

Youssef

Scola

Lorenzoni

et al. 2009

Arq. Neuro-Psiquiatr.

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-Nemaline myopathy (NM) is a congenital disease that leads to hypotonia and feeding difficulties in neonates. Some cases have a more benign course, with skeletal abnormalities later in life. We analyzed a series of eight patients with NM obtained from a retrospective analysis of 4300 muscle biopsies. Patients were classified as having the typical form in five cases, intermediate form in two cases and severe form in one case. Histochemical analysis showed mixed rods distribution in all cases and predominance of type I fibers in five cases. Immunohistochemical analysis showed abnormal nebulin expression in all patients (four heterogeneous and four absent), homogeneous desmin expression in four cases, strongly positive in three and absent in one, fast myosin expression in a mosaic pattern in six cases and absent in two cases. There was no specific relation between these protein expression patterns and the clinical forms of NM.KEY WORDS: nemaline myopathy, nebulin, desmin, myosin, immunohistochemistry. miopatia nemalínica: achados clínicos, histoquímicos e imuno-histoquímicosResumo -Miopatia nemalínica (NM) é uma doença congênita que leva a hipotonia e dificuldade de sugar em neonatos. Alguns casos possuem uma evolução benigna, com deformidades ósseas tardias. Nós analisamos uma série de oito pacientes com NM obtidos da análise retrospectiva de 4300 biópsias musculares. Os pacientes foram classificados como forma típica em cinco casos, forma intermediária em dois casos e forma severa em um caso. Análise histoquímica mostrou distribuição mista dos rods em todos os casos e predominância de fibras tipo I em cinco casos. Análise imuno-histoquímica mostrou expressão anormal da nebulina em todos os pacientes (quatro heterogênea e quatro ausente), expressão homogenea da desmina em quatro casos, fortemente positiva em tres e ausente em um, expressão da miosina (rápida) com padrão em mosaico em seis casos e ausente em dois casos. Não há relação específica entre a expressão destas proteínas e as formas clínicas da NM.

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“…TPM2 is expressed in both slow (type 1), and, to a lesser extent, fast (type 2) muscle fibres, whereas TPM3 encodes the slow-specific isoform aTm slow . 25 Mutations in slow muscle fibre-specific TPM3 cause NM 6,13,17,18,26 and have recently been shown to perhaps be a relatively common cause of congenital fibre type disproportion (CFTD), 27 while mutations of TPM2, expressed in all muscle fibres, have been reported in patients either with NM, 7 distal arthrogryposis, 28 or cap disease. 29 TPM1 mutations are known to cause dilated and hypertrophic cardiomyopathies (MIM 115196).…”

Section: Discussionmentioning

confidence: 99%

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

et al. 2008

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To date, six genes are known to cause nemaline (rod) myopathy (NM), a rare congenital neuromuscular disorder. In an attempt to find a seventh gene, we performed linkage and subsequent sequence analyses in 12 Turkish families with recessive NM. We found homozygosity in two of the families at 1q12-21.2, a region encompassing the c-tropomyosin gene (TPM3) encoding slow skeletal muscle a-tropomyosin, a known NM gene. Sequencing revealed homozygous deletion of the first nucleotide of the last exon, c.913delA of TPM3 in both families. The mutation removes the last nucleotide before the stop codon, causing a frameshift and readthrough across the termination signal. The encoded aTm slow protein is predicted to be 73 amino acids longer than normal, and the extension to the protein is hypothesised to be unable to form a coiled coil. The resulting tropomyosin protein may therefore be non-functional. The affected children in both families were homozygous for the mutation, while the healthy parents were mutation carriers. Both of the patients in Family 1 had the severe form of NM, and also an unusual chest deformity. The affected children in Family 2 had the intermediate form of NM. Muscle biopsies showed type 1 (slow) fibres to be markedly smaller than type 2 (fast) fibres. Previously, there had been five reports, only, of NM caused by mutations in TPM3. The mutation reported here is the first deletion to be identified in TPM3, and it is likely to be a founder mutation in the Turkish population.

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Mutations in TPM3 are a common cause of congenital fiber type disproportion

Abstract: Mutation of TPM3 is the most common cause of CFTD reported to date.

Cited by 156 publications

References 26 publications

Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping

Further Delineation of the Phenotype of Congenital Disorder of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping

Nemaline myopathy: clinical, histochemical and immunohistochemical features

Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin

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