Skip to Main content Skip to Navigation
Journal articles

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

Abstract : OBJECTIVE: Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding alpha-tropomyosin(slow) (TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD. METHODS AND RESULTS: We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant. INTERPRETATION: Mutation of TPM3 is the most common cause of CFTD reported to date.
Document type :
Journal articles
Complete list of metadata

Cited literature [27 references]  Display  Hide  Download
Contributor : Nathalie Roux-Buisson <>
Submitted on : Friday, February 19, 2010 - 12:01:47 PM
Last modification on : Thursday, December 10, 2020 - 12:36:14 PM
Long-term archiving on: : Wednesday, November 30, 2016 - 9:51:50 AM


 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document




Nigel Clarke, Hanna Kolski, Danielle Dye, Esther Lim, Robert Smith, et al.. Mutations in TPM3 are a common cause of congenital fiber type disproportion.. Annals of Neurology, Wiley, 2008, 63 (3), pp.329-37. ⟨10.1002/ana.21308⟩. ⟨inserm-00410305⟩



Record views