Abstract
TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.
Highlights
Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase, whose activity is contained in the RING finger domain of the tripartite TRIM/RBCC motif (RING, B-box, coiled-coil) [20, 30]
Mutations in NHL, coiled-coil and RING domains of TRIM32 are found in patients with a muscular dystrophy We studied three independent families of Spanish and Australian origin with a muscular dystrophy (Fig. 1a), and identified four novel TRIM32 mutations located in three different domains; NHL, coiled-coil and RING domains
Our results demonstrate a common pathogenic pathway in the development of muscular dystrophy associated to TRIM32 mutations which lead to loss or reduction of the protein
Summary
Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase, whose activity is contained in the RING finger domain of the tripartite TRIM/RBCC motif (RING, B-box, coiled-coil) [20, 30]. The majority of the mutations described in TRIM32 are clustered in the C-terminal NHL domain, which is defined by amino acid sequence homologies to regions of Ncl-1, HT2A and Lin-41 proteins, supporting its role in protein-protein interactions, critical for the ubiquitination process [13, 29, 44]. Only one mutation has been described involving the B-box domain, resulting in a different multisystemic disorder called Bardet-Biedl syndrome (BBS) type 11 with no skeletal muscle involvement, in an only family with four affecting siblings [7]. No mutations in the RING finger domain have been reported
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